N22-117S018; S019 Asenapine Clinical BPCA · 2015. 1. 8. · • P06107-0018-100475. 6 Reference...

CLINICAL REVIEW

Application Type sNDA Application Number 22-117 S-019 Priority or Standard Priority

Submit Date September 12 2014 Received Date September 12 2014

PDUFA Goal Date March 12 2015 Division Office DPPODE I

Reviewer Name Greg Dubitsky MD Review Completion Date February 17 2015

Established Name Asenapine Trade Name Saphris

Therapeutic Class Antipsychotic Applicant Forest Laboratories

Formulation Sublingual Tablets Dosing Regimen 25mg BID to 10mg BID

Indication Bipolar I DO (manic or mixed) Intended Population Pediatric Patients (ages 10-17)

Template Version March 6 2009

Reference ID 3703398

Clinical Review Greg Dubitsky MD NDA 22-117 S-019 Saphris (asenapine)

Table of Contents

1 RECOMMENDATIONSRISK BENEFIT ASSESSMENT 4

11 Recommendation on Regulatory Action 4 12 Risk Benefit Assessment 4 13 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies 4 14 Recommendations for Postmarket Requirements and Commitments 4

2 INTRODUCTION AND REGULATORY BACKGROUND 4

21 Product Information 4 22 Tables of Currently Available Treatments for Proposed Indications 4 23 Availability of Proposed Active Ingredient in the United States 5 24 Important Safety Issues With Consideration to Related Drugs 5 25 Summary of Presubmission Regulatory Activity Related to Submission 5 26 Other Relevant Background Information 6

3 ETHICS AND GOOD CLINICAL PRACTICES 6

31 Submission Quality and Integrity 6 32 Compliance with Good Clinical Practices 7 33 Financial Disclosures 7

4 SIGNIFICANT EFFICACYSAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES 9

44 Clinical Pharmacology 9 441 Mechanism of Action 9 442 Pharmacodynamics 9 443 Pharmacokinetics 9

5 SOURCES OF CLINICAL DATA 10

51 Tables of StudiesClinical Trials 10 52 Review Strategy 11

6 REVIEW OF EFFICACY 11

Efficacy Summary 11 61 Efficacy in Pediatric Schizophrenia 11

611 Methods 11 612 Demographics 13 613 Subject Disposition 13 614 Analysis of the Primary Endpoint 14 615 Analysis of the Key Secondary Endpoints 15 616 Other Endpoints 16 617 Subpopulations 17 618 Analysis of Clinical Information Relevant to Dosing Recommendations 20 619 Discussion of Persistence of Efficacy andor Tolerance of Effects 20

2



6110 Additional Efficacy IssuesAnalyses 21

7 REVIEW OF SAFETY 21

Safety Summary 21 71 Methods 23

711 StudiesClinical Trials Used to Evaluate Safety 23 712 Categorization of Adverse Events 23 713 Pooling of Data Across StudiesClinical Trials to Estimate and Compare

Incidence 23 72 Adequacy of Safety Assessments 24

721 Overall Exposure at Appropriate DosesDurations and Demographics of Target Populations 24

722 Explorations for Dose Response 25 724 Routine Clinical Testing 25 726 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class 26

73 Major Safety Results 26 731 Deaths 26 732 Nonfatal Serious Adverse Events 26 733 Dropouts andor Discontinuations 27 734 Significant Adverse Events 28 735 Submission Specific Primary Safety Concerns 37

74 Supportive Safety Results 38 741 Common Adverse Events 38 742 Laboratory Findings 40 743 Vital Signs 48 744 Electrocardiograms (ECGs) 53

75 Other Safety Explorations 58 751 Dose Dependency for Adverse Events 58 753 Drug-Demographic Interactions 58

76 Additional Safety Evaluations 59 762 Human Reproduction and Pregnancy Data 59 763 Pediatrics and Assessment of Effects on Growth 60 764 Overdose Drug Abuse Potential Withdrawal and Rebound 63

8 POSTMARKET EXPERIENCE 63

9 APPENDICES 64

91 Literature ReviewReferences 64 92 Labeling Recommendations 65 93 Advisory Committee Meeting 65

3



1 RecommendationsRisk Benefit Assessment

11 Recommendation on Regulatory Action

It is recommended that this supplement be approved for the use of asenapine in the treatment of manic or mixed episodes associated with bipolar I disorder in pediatric patients ages 10-17

12 Risk Benefit Assessment

The benefits of asenapine treatment of pediatric patients with manic or mixed mood episodes associated with bipolar I disorder are felt to outweigh the risks

13 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies

None are recommended at this time

14 Recommendations for Postmarket Requirements and Commitments

No further PMRs or PMCs are recommended

2 Introduction and Regulatory Background

21 Product Information

Asenapine is an atypical antipsychotic that was first approved in the US under the tradename Saphris on August 13 2009 It is approved for the treatment of schizophrenia and for the acute treatment either as monotherapy or adjunctive therapy of manic or mixed episodes associated with bipolar I disorder The approval of these indications was based on clinical trials in adult patients

22 Tables of Currently Available Treatments for Proposed Indications

Currently approved treatments for manic or mixed episodes in pediatric patients with bipolar I disorder include Risperdal (risperidone) Abilify (aripiprazole) Seroquel XR (quetiapine extended-release) and Zyprexa (olanzapine) These drugs were studied in patients ages 10-17 years except for Zyprexa which was studied in 13-17 year olds

4



23 Availability of Proposed Active Ingredient in the United States

Asenapine has been available in the US since 2009

24 Important Safety Issues With Consideration to Related Drugs

Important risks associated with the use of atypical antipsychotics are

bull metabolic changes including hyperglycemia and diabetes mellitus dyslipidemia and weight gain bull cerebrovascular events (eg stroke) in elderly patients with dementia-related psychosis bull orthostatic hypotension and syncope bull neuroleptic malignant syndrome bull tardive dyskinesia bull leukopenia neutropenia and agranulocytosis

25 Summary of Presubmission Regulatory Activity Related to Submission

The approval of Saphris in 2009 carried a number of Postmarketing Requirements (PMRs) for pediatric trials to satisfy PREA requirements

PMR 1496-1 - a deferred study to obtain pharmacokinetic (PK) data and provide information relevant to asenapine dosing in pediatric patients (ages 13-17) with schizophrenia

PMR 1496-2 - a deferred study of the efficacy and safety of asenapine in pediatric patients (ages 13-17) with schizophrenia

PMR 1496-3 - a deferred study to obtain pharmacokinetic (PK) data and provide information relevant to asenapine dosing in pediatric patients (ages 10-17) with manic or mixed episodes associated with bipolar I disorder

PMR 1496-4 - a deferred study of the efficacy and safety of asenapine in pediatric patients (ages 10-17) with manic or mixed episodes associated with bipolar I disorder

A waiver of PREA study requirements for ages 0-12 years for schizophrenia and 0-9 years for bipolar I disorder was granted because studies would be highly impractical because of the low incidence of disease in those age ranges

A Written Request (WR) to obtain pediatric information on the use of asenapine in patients (ages 13-17) with schizophrenia and in patients (ages 10-17) with bipolar I disorder was issued by the Agency on September 23 2009 The WR was formally

5



amended on June 2 2010 October 22 2010 and August 30 2013 An administrative editorial change to the last amendment was issued on February 6 2014

Trials intended to address PMR 1496-3 and PMR 1496-4 as well as the requirements of the WR with respect to bipolar disorder were conducted under IND 70329

A pre-sNDA teleconference was held with the sponsor on July 23 2013 The planned supplement would encompass a total of 6 trials 2 PK studies of asenapine in pediatric patients 2 trials in patients ages 12-17 with schizophrenia (an 8-week RCT and a 26shyweek open label study) and 2 trials in patients ages 10-17 with bipolar I disorder (a 3shyweek RCT and a 26 plus-week open-label study) An admonition against pooling safety data because of the diverse designs of these trials was communicated to the sponsor The Agency had no objection to including 12 year old and 18 year old patients in the analyses for trial P05896 and 12 year old patients in the analyses of trial P05897 The Agency also advised the sponsor to propose an amendment to the WR to clarify that the minimum number of patients exposed for 6 months (N=100) could be derived from the pool of the two long-term studies in schizophrenia and bipolar disorder and not that number from each study Other advice pertained to the evaluation of demographic factors on efficacy and safety findings the analysis of C-SSRS data and information regarding investigational sites to be submitted to the Office of Scientific Investigations (OSI) regarding clinical site inspections

This supplement is intended to convey the information accrued from the 4 trials relevant to bipolar disorder

26 Other Relevant Background Information

On January 31 2014 the Agency was notified that ownership of NDA 22-117 had been transferred from Organon USA Inc a subsidiary of Merck Sharp amp Dohme Corp to Forest Laboratories Inc

3 Ethics and Good Clinical Practices

31 Submission Quality and Integrity

The consistency of adverse event information in this application was evaluated by comparing information across the following documents for a sample of 6 patients from the two Phase 3 bipolar trials Case Report Forms (CRFs) Narrative Summaries (NSs) and adverse event data listings (aexpt files) The 6 patients audited were

bull P06107-0010-100123 bull P06107-0018-100461 bull P06107-0018-100475

6




Adverse event data was found to be consistently documented for these patients

Additionally the sponsorrsquos coding of adverse event verbatim terms (AELIT) to preferred terms (AEDECOD) as documented in the adverse event data files (aexpt) for trials P06107 and P05898 was audited No inaccuracies in adverse event coding were detected However as will be discussed in Section 712 because MedDRA allows splitting of closely related verbatim terms to multiple coded terms related preferred terms have been combined into common terms for purposes of this review

32 Compliance with Good Clinical Practices

Trials P06107 and P05898 were both conducted in accordance with Good Clinical Practice standards

I requested that the Office of Scientific Investigations (OSI) conduct inspections of sites 18 and 45 in trial P06107 These sites were inspected on January 12-15 2015 and January 12-21 2015 respectively A Clinical Inspection Summary was completed on February 9 2015 by Dr Jenn W Sellers of OSI There were no deviations from regulations identified and the data from both sites were felt to be acceptable The preliminary classification for both sites was NAI

33 Financial Disclosures

Clinical Investigator Financial Disclosure Review Template

Application Number 22-117 S-019

Submission Date(s) September 12 2014

Applicant Forest Laboratories

Product Saphris

Reviewer Greg Dubitsky MD

Date of Review February 17 2015

Covered Clinical Study (Name andor Number) P06107

Was a list of clinical investigators provided Yes No (Request list from applicant)

7



Total number of investigators identified 92

Number of investigators who are sponsor employees (including both full-time and part-time employees) 0

Number of investigators with disclosable financial interestsarrangements (Form FDA 3455) 0

If there are investigators with disclosable financial interestsarrangements identify the number of investigators with interestsarrangements in each category (as defined in 21 CFR 542(a) (b) (c) and (f))

Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study Significant payments of other sorts Proprietary interest in the product tested held by investigator Significant equity interest held by investigator in sponsor of covered study

Is an attachment provided with details of the disclosable financial interestsarrangements

Yes No (Request details from applicant)

Is a description of the steps taken to minimize potential bias provided

Yes No (Request information from applicant)

Number of investigators with certification of due diligence (Form FDA 3454 box 3) 0

Is an attachment provided with the reason

Yes No (Request explanation from applicant)

Discuss whether the applicant has adequately disclosed financial interestsarrangements with clinical investigators as recommended in the guidance for industry Financial Disclosure by Clinical Investigators Also discuss whether these interestsarrangements investigators who are sponsor employees or lack of disclosure despite due diligence raise questions about the integrity of the data

- If not why not (eg study design (randomized blinded objective endpoints) clinical investigator provided minimal contribution to study data)

- If yes what steps were taken to address the financial interestsarrangements (eg statistical analysis excluding data from clinical investigators with such interestsarrangements)

Briefly summarize whether the disclosed financial interestsarrangements the inclusion of investigators who are sponsor employees or lack of disclosure despite due diligence affect the approvability of the application

8



No investigators in trial P06107 had disclosable financial information

4 Significant EfficacySafety Issues Related to Other Review Disciplines

44 Clinical Pharmacology

441 Mechanism of Action

There is no new information in this supplement regarding the mechanism of action of asenapine in treating schizophrenia

442 Pharmacodynamics

There is no new information on the pharmacodynamics of asenapine

443 Pharmacokinetics

The sponsor conducted two studies to explore the safety and PK of asenapine in the pediatric population (A70501022 and P06522) In addition a pediatric population PK analysis was performed using data from these two PK studies and from the 2 pediatric RCTs one in schizophrenia (P05896) and one in bipolar I disorder (P06107) to develop a population PK model for asenapine in pediatric patients

Study A70501022 was a randomized double-blind placebo-controlled parallel group study of multiple dose sublingual asenapine in 40 adolescents (ages 12-17) with a psychotic disorder Doses of 1 3 5 and 10mg q12 hours were administered for 10 days Eight patients took asenapine and 2 took placebo in each dose group

Study P06522 was an open-label rising multiple dose study in 30 patients age 10-17 years with schizophrenia or a manic or mixed episode associated with bipolar I disorder Patients with autism conduct disorder oppositional defiant disorder or other condition requiring antipsychotic treatment were allowed in some cohorts Patients ages 10-11 (N=6) were treated with in sequential sublingual asenapine dose groups of 25mg bid for 7 days 5mg bid for 7 days or 10mg bid for 12 days (N=6 per cohort) with a decrease from 10 to 5mg bid for 7 days if intolerance emerged in the 10mg bid cohort Patients ages 12-17 received a sublingual dose of 10mg bid for 8 days in 3 parallel age cohorts (12-13 14-15 and 16-17) with 4 patients per cohort

The Office of Clinical Pharmacology (OCP) reviewer Dr Andre Jackson concluded that asenapine exposure was similar in adults adolescents and children 10-11 years old

9



5 Sources of Clinical Data

51 Tables of StudiesClinical Trials

The following studies were conducted to support a claim for manic and mixed mood episodes associated with bipolar I disorder in the pediatric population

Table 1 Table of Studies in Pediatric Bipolar Disorder PhaseStudy Study Design

Phase 1 A70501022 Randomized double-blind placebo-controlled parallel group safety

and PK study of multiple dose asenapine in 40 adolescents (ages 12-17) with a psychotic disorder Dosing was 1 3 5 and 10mg q12 hours for 10 days

P06522 Open-label rising multiple dose safety and PK study in 30 patients (ages 10-17) primarily with schizophrenia or bipolar I disorder Dosing was 25 5 and 10 mgday for 7-12 days

Phase 3 P06107 3-week randomized double-blind placebo-controlled safety and

efficacy trial in 403 patients (ages 10-17) with manic or mixed mood episodes associated with bipolar I disorder using fixed doses of 25mg BID 5mg BID 10mg BID or placebo

P05898 50-week open-label extension safety study for completers of trial P06107 using flexible dosing with 25mg BID to 10mg BID

Hereafter in this review the 25mg BID 5mg BID and 10mg BID doses will be referred to as 25mg 5mg and 10mg respectively

This information was contained in the following submissions

Table 2 Submissions to the sNDA Submission Date Sequence Contents

Sep 12 2014 0171 Original sNDA Jan 8 2015 0196 Four-Month Safety Update Report

Jan 21 2015 0197 Requested conversion of laboratory data from SI to conventional units

Jan 23 2015 0198 Requested information regarding the sponsorrsquos literature search and cumulative exposure

Feb 3 2015 0201 Requested patient laboratory data

10



52 Review Strategy

The efficacy review of this supplement is based solely on the results of trial P06107

The safety review of this supplement is comprised of two components 1) an examination of serious adverse events (SAEs) and adverse events that led to dropout in all 4 studies (including limited safety information from study P05898 contained in the Four-Month Safety Update Report submitted on January 8 2015) and 2) an evaluation of supportive safety findings from analyses of data primarily from trial P06107 to include an assessment of common adverse events laboratory tests vital signs and ECGs

6 Review of Efficacy Efficacy Summary The efficacy of asenapine 25mg BID 5mg BID and 10mg BID in patients ages 10-17 with bipolar disorder in a manic or mixed state was evaluated in one clinical trial (P06107) Superiority over placebo was demonstrated for all three doses on both the primary endpoint (change from baseline to Day 21 in the Young-Mania Rating Scale (YshyMRS)) and the key secondary endpoint (change from baseline to Day 21 in the CGI-Bipolar (CGI-BP) score) after appropriate adjustment for multiple comparisons In terms of dose-response the 5mg BID dose was superior to 25mg BID but approximately equal to the 10mg BID dose The biometrics reviewer Dr Jialu Zhang completed a Statistical Review and Evaluation on February 5 2015 and concurs with this conclusion

61 Efficacy in Pediatric Schizophrenia

611 Methods

The demonstration of the efficacy of asenapine in pediatric patients (ages 12-17) with bipolar disorder is based on a single clinical trial (P06107) Because asenapine is approved for the treatment of adults with bipolar disorder and it is felt that bipolar illness is essentially the same in older children adolescents and adults a single efficacy trial is deemed to be sufficient

P06107 was an 3-week randomized double-blind placebo-controlled parallel group trial This investigation was conducted at 58 sites in the US and 9 sites in Russia

Important inclusion criteria for this trial were

bull age ge10 years when providing assentconsent and le17 years when randomized

11



bull diagnosis of bipolar I disorder in a current manic or mixed state by DSM-IV-TR criteria confirmed by a structured clinical interview (K-SADS-PL) at screening bull at least one manic-specific symptom elation grandiosity flight of ideasracing thoughts decreased need for sleep or hypersexuality bull Y-MRS total score ge20 at screening and baseline bull CGI-BPoverall severity score ge4 at screening and baseline

Relevant exclusion criteria were

bull diagnosis of a psychotic disorder bull known or suspected mental retardation organic brain disorder or an IQ lt70 bull meets DSM-IV-TR criteria for substance abuse or dependence (except for nicotine or caffeine) within the prior 6 months bull behavioral disturbance thought to be substance-induced bull at imminent risk of self-harm or harm to others in the opinion of the investigator bull suicidal ideation with intent with or without a plan in the past 2 months or suicidal behavior in the past 6 months as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) bull history of tardive dyskinesia tardive dystonia or NMS bull an uncontrolled or unstable and clinically significant medical condition that might interfere with safety and efficacy evaluations in the investigatorrsquos opinion bull females who are pregnant or breast-feeding or intend to become pregnant during the course of the trial bull known or suspected seizure disorder bull unwillingness or inability to taper off prohibited medication

Eligible patients were randomized in a 1111 ratio to treatment with asenapine 25mg BID asenapine 5mg BID asenapine 10mg BID or placebo (referred to as the 25mg 5mg 10mg and placebo groups respectively) All treatments were supplied as fast-dissolving black cherry-flavored sublingual tablets to be taken daily at approximately 8AM and 8PM Patients assigned to the 5mg group received 25mg BID until their Day 4 visit when the dose was increased to 5mg BID and continued until the end of the treatment period Patients assigned to the 10mg group received 25mg BID until their Day 4 visit when the dose was increased to 5mg BID and continued until Day 7 On Day 7 these patients began 10mg BID which was continued to the end of the treatment period

The primary efficacy variable was the change from baseline to Day 21 in the Y-MRS total score The key secondary measure was the change from baseline to Day 21 in the severity of bipolar illness as measured by the CGI-BPoverall Both the primary and key secondary assessments were performed at screening and baseline and on Days 4 7 14 and 21 The statistical analysis for both was done using MMRM (Mixed Model for Repeated Measures) on the FAS (Full Analysis Set defined as all randomized patients who received at least one dose of trial medication and had a baseline and at least one

12



post-baseline on-treatment Y-MRS assessment) Multiplicity adjustment for the three comparisons (25mg vs placebo 5mg vs placebo and 10mg vs placebo) was performed using the Hochberg procedure with a 2-sided alpha level of 5 Only if the primary efficacy null hypothesis is rejected for all three comparisons would the key secondary hypotheses be tested

The trial was monitored by an independent external Data Monitoring Committee (DMC) on an ongoing basis to evaluate the trial safety data among other responsibilities and to make recommendations as to whether the study should continue to recruit patients be modified or be terminated The DMC consisted of 4 voting members representing the fields of psychiatry and statistics

612 Demographics

Overall almost half of the study patients were male (47) but these was some variation in gender composition across the treatment groups (range of 38 to 59 male) The treatment groups were reasonably well-balanced in terms of age race and ethnicity The mean age across all groups was 138 years with 72 over the age of 12 years Racially the most common group was white (68) followed by Black or African American (24) About 88 were classified as not Hispanic or Latino in terms of ethnicity US patients made up 94 of the patient sample

Most of the patients (58) were in a mixed mood state at study entry with 42 in a manic state For the majority of the patients (61) the current episode had lasted more than 4 weeks Only 33 were naive to antipsychotic medication About 12 were classified as rapid cyclers (ge4 mood episodes in the previous 12 months)

613 Subject Disposition

Patient disposition is displayed in the table below About 87 of all patients completed the trial with 80 continuing treatment in the extension trial Completion rates were comparable across treatment groups The most common reason for dropout overall was because of an adverse event which occurred more frequently in the asenapine groups than in the placebo group Kaplan-Meier plots of discontinuation over time were similar across the four treatment groups

13



Table 3 Subject Disposition (P06107)

The FAS consisted of 395 patients (or 98 of those randomized) 98 in the placebo group and 101 98 and 98 in the 25mg 5mg and 10mg groups respectively

614 Analysis of the Primary Endpoint

Results on the primary efficacy endpoint are summarized in the following table

Table 4 Change From Baseline to Day 21 in the Y-MRS (P06107)

The following figure depicts the mean change from baseline in the Y-MRS over time

14



Figure 1 LS Mean Change from Baseline (95 CI) in the Y-MRS By Visit (P06107) (FAS)

All three asenapine dose groups demonstrated statistically significant superiority over placebo on the primary efficacy endpoint after adjustment for multiple comparisons The 5mg BID dose was numerically superior to the 25mg BID dose but roughly equal to the 10mg group

615 Analysis of the Key Secondary Endpoints

The key secondary measure was the change from baseline to Day 21 in the CGI-BP overall score Results on this endpoint are displayed in the table below

15



Table 5 Change from Baseline to Day 21 in the CGI-BP Overall Score (P06107)

All three dose groups demonstrated statistically significant superiority over placebo after adjustment for multiplicity on the key secondary endpoint

616 Other Endpoints

Other secondary endpoints included the Y-MRS responder rate and the Y-MRS remitter rate A responder was defined as a patient who experienced at least a 50 decrease from baseline in the Y-MRS total score At endpoint the percentages of FAS patients who met the responder criterion were

Placebo 28 (2798) Asenapine 25mg 42 (42101) Asenapine 5mg 54 (5398) Asenapine 10mg 52 (5198)

A remitter was defined as a patient who had a Y-MRS total score le12 At endpoint the percentages of FAS patients who met the remitter criterion were


16



These results follow the same pattern as the findings on the primary and key secondary endpoints

617 Subpopulations

The sponsor conducted analyses of the potential effects of subgroup features (eg age gender race region cycling frequency previous antipsychotic treatment) on the average treatment effect of asenapine versus placebo on the primary efficacy variable (change from baseline to day 21 in the Y-MRS total score) The results shown in the following table revealed no statistically significant differences between subgroups (alpha =010)

17



Table 6 Change From Baseline to Day 21 in the Y-MRS Score By Subgroup (Trial P06107)

18



Table 6 Change From Baseline to Day 21 in the Y-MRS Score By Subgroup (continued)

19




618 Analysis of Clinical Information Relevant to Dosing Recommendations

The sponsor evaluated dose-response for efficacy by examining 7 possible dose response patterns across the four treatment groups based on adjusted p-values for the primary endpoint The pattern that best fit the data was a sequential increase in response from placebo to 25mg BID to 5mg BID with an equal response for 5mg BID and 10mg BID

619 Discussion of Persistence of Efficacy andor Tolerance of Effects

A trial to evaluate asenapine in the maintenance of efficacy in bipolar disorder in adults

forwarded to the Agency by October 31 2015 is ongoing in response to PMC 1496-5 It is expected that the study report will be

(b) (4)

20



50-week open label study (P05898) most of the serious adverse events were psychiatric in nature the most commonly reported being suicidal ideation (8 patients) aggression bipolar disorder and depression (3 patients each) and agitation (2 patients)

The most common adverse events that led to dropout in trial P06107 were somnolence abdominal pain and nausea As of the cutoff for the Four-Month Safety Update Report adverse events that led to dropout in the open-label study P05898 (total N=321) were mostly psychiatric in nature aggression and suicidal ideation (3 patients each) and anxiety ADHD bipolar disorder depression depressive symptom irritability and suicidal behavior (2 patients each)

Other significant safety findings were

bull hyperglycemia new onset diabetes mellitus and metabolic syndrome bull dyslipidemia (increased cholesterol and triglycerides relative to placebo) bull increased body weight bull hypersensitivity reactions bull hyperprolactinemia bull somnolence bull extrapyramidal symptoms (akathisia and Parkinsonism) bull oral hypoesthesia

The most common adverse events felt to be probably drug-related were oral paresthesia nausea fatigue weight increased increased appetite somnolence dizziness and dysgeusia Only fatigue and dysgeusia are considered possibly dose-related

Remarkable laboratory test abnormalities associated with asenapine treatment were an increased mean change in platelet count and liver enzymes (SGPT SGOT and GGT) and a greater proportion of asenapine- versus placebo-treated patients with decreases in white blood cell and neutrophil counts and increased SGPT levels

Vital sign changes associated with asenapine treatment were increased mean changes in standing diastolic blood pressure (about 2 mmHg) and increased supine pulse (2-4 bpm)

Most of these safety findings are already known to be associated with asenapine treatment and are labeled There are no new findings that suggest a hazard which would preclude approval of this supplement or require a major labeling change

22



71 Methods

711 StudiesClinical Trials Used to Evaluate Safety

Safety data were derived primarily from studies P06107 and P05898

712 Categorization of Adverse Events

Adverse event verbatim terms were coded to preferred terms using MedDRA version 160 Although an audit of this coding process revealed no major inaccuracies the granularity of MedDRA does allow splitting of some adverse event terms to an extent that may not be clinically useful Therefore for purposes of this review the following related adverse event preferred terms were subsumed under a common term for calculation of reporting rates in the following sections

Common Term Subsumed Preferred Terms Somnolence Somnolence sedation hypersomnia

Abdominal pain Abdominal pain abdominal pain upper abdominal pain lower abdominal discomfort

Bipolar disorder Bipolar disorder bipolar I disorder mania mood swings tachyphrenia

Hyperinsulinemia Hyperinsulinemia blood insulin increased Tachycardia Tachycardia heart rate increased

Fatigue Fatigue lethargy Leukopenia Leukopenia neutropenia white blood cell count

decreased

Adverse events were also categorized as serious or non-serious Serious adverse events (SAEs) were defined by one of the following criteria

bull results in death bull life-threatening (at immediate risk of death at the time of the occurrence) bull requires inpatient hospitalization or prolongs inpatient hospitalization bull results in persistent or significant disability or incapacity bull congenital abnormality or birth defect bull other important medical events that is events not meeting any of the above criteria but which may jeopardize the subject and may require medical or surgical intervention to prevent one of the above outcomes

713 Pooling of Data Across StudiesClinical Trials to Estimate and Compare Incidence

Because of the significant differences in study design between the 2 trials in the pediatric bipolar program studies were not pooled

23



72 Adequacy of Safety Assessments

721 Overall Exposure at Appropriate DosesDurations and Demographics of Target Populations

For purposes of evaluating exposure in the pediatric population the 4 Phase 3 trials in pediatric patients were pooled in accordance with the Written Request

bull P05896 - 8-week randomized double-blind placebo-controlled study in schizophrenic patients (ages 12-17) bull P05897 - 26-week open-label extension to P05896 bull P06107 - 3-week randomized double blind placebo-controlled study in patients with manic or mixed episodes associated with bipolar I disorder (ages 10-17) bull P05898 - 50-week ongoing open-label extension to P06107

Across these 4 trials patients were treated with sublingual asenapine in the dose range of 25mg BID to 10mg BID As of October 31 2014 (the cutoff date for the Four-Month Safety Update Report) a total of 651 patients received asenapine treatment for any duration 352 received asenapine for 180 days or longer and 58 received asenapine for 365 days or longer

Demographic characteristics of patients in trial P06107 were generally consistent across the four treatment groups (placebo and asenapine 25mg 5mg and 10mg) with the exception of gender which displayed moderate variability

Dose Group Percentage of Females Placebo 62 25mg 50 5mg 57 10mg 41

Overall the median age was 140 years with 28 age 12 or younger The most common racial groups were white (68) and Black or African American (24) Ethnically most patients (88) were classified as not Hispanic or Latino Most of the patients were from US sites (94) The mean baseline weight and BMI percentiles adjusted for age and sex were 70 and 72 respectively In terms of height the mean percentile adjusted for age and sex was 50 So although patients tended to be of average height they were heavier for their age and sex The distribution of patients by age is shown in the figure below

24



Figure 2 Number of Patients By Age (Trial P06107)

Age (years)

There was a reasonable distribution of patients across ages in this trial

722 Explorations for Dose Response

The fixed dose design of trial P06107 permitted an assessment of the dose-response relationship for safety findings

724 Routine Clinical Testing

In addition to adverse event assessments safety measurements in trial P06107 include the following

bull laboratory testing at screening and baseline and on day 21 Inpatients provided blood samples prior to breakfast and outpatients were instructed to fast overnight if possible Laboratory tests consist of hematology (including total WBC counts as well as neutrophil monocyte eosinophil and lymphocyte counts) chemistry (including ALT AST alkaline phosphatase total bilirubin electrolytes BUN and creatinine) lipid and

25



endocrine parameters (including glucose total cholesterol LDL HDL triglycerides HbA1c and prolactin) and urinalysis bull orthostatic pulse and blood pressure were measured at screening and baseline and on days 4 7 14 and 21 bull 12-lead ECGs were done at screening and on day 21 bull Columbia-Suicide Severity Rating Scale (C-SSRS) was assessed at screening and baseline and on days 1 4 7 14 and 21 bull Extrapyramidal Symptom Rating Scale (ESRS) was conducted at baseline and on days 7 14 and 21 The ESRS evaluates symptoms of parkinsonism akathisia dystonia and dyskinesia bull height (measured by stadiometer) weight and girth were measured at screening and baseline and on days 4 7 14 and 21 bull Childrenrsquos Depression Rating Scale-Revised (CDRS-R) was assessed at baseline and on days 7 14 and 21 to monitor for the emergence of depression bull Tanner stage was assessed at screening and on day 21 bull a cognitive battery was administered prior to randomized treatment and on day 21 This battery consisted of the following tests Color Word Interference Task Letter Fluency Semantic Fluency Auditory Number Sequencing and the Strategic Target Detection Test These assessments are described in more detail below

726 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class

The above assessments are expected to be adequate to detect potential adverse effects seen with similar drugs in this class for example metabolic changes orthostatic hypotension neutropenia and tardive dyskinesia

73 Major Safety Results

731 Deaths

No deaths occurred during the Phase 3 bipolar trials P06107 or P05898 or in the Phase 1 studies A7501022 and P06522 as of October 31 2014 the cutoff for the Four-Month Safety Update Report

732 Nonfatal Serious Adverse Events

There were no non-fatal SAEs in the Phase 1 studies A7501022 and P06522 In trial P06107 there were 7 patients with SAEs 3 patients in the placebo group and 2 each in the 5mg and 10mg groups All seven patients had events in the psychiatric System Organ Class which represented either probable worsening of bipolar illness or suicidal ideation or behavior After combining similar terms the numbers of patients with each type of serious adverse event were

26



Placebo 25mg 5mg 10mg Suicidal IdeationBehavior 1 0 0 1 Bipolar Disorder Worsening 2 0 2 1

As reported in the Four-Month Safety Update Report in the open-label study P05898 7 (22321) of patients had experienced SAEs Most of the SAEs were psychiatric in nature the most commonly reported being suicidal ideation (8 patients) aggression bipolar disorder and depression (3 patients each) and agitation (2 patients) Other SAEs that were reported in one patient each were anxiety disturbance in social behavior exhibitionism impulsive behavior mania self-injurious behavior suicidal ideation accidental overdose intentional overdose dystonia loss of consciousness somnolence and drug hypersensitivity (swollen tongue) Tongue swelling is currently described in Saphris labeling The case of loss of consciousness occurred in a 12 year old male (67100202) in the context of an accidental Ambien overdose

733 Dropouts andor Discontinuations

In the Phase 1 studies A7501022 and P06522 there was only one dropout because of an adverse event (exacerbation of schizophrenia)

The percentages of patients who dropped out of trial P06107 because of adverse events are displayed in the following table As mentioned above certain closely related adverse event preferred terms were combined into common terms to enhance the clinical usefulness of event reporting rates Common adverse events associated with dropout in trial P06107 and the corresponding proportions of patients who discontinued study treatment because of those events were

Common Term Placebo 25mg 5mg 10mg Somnolence 0 3 1 2

Abdominal pain 0 0 0 2 Bipolar disorder 2 0 2 0

Adverse events after combining terms that led to dropout in at least 2 of patients in any asenapine arm (before rounding) at a rate at least twice the placebo rate were somnolence abdominal pain and nausea

As of the cutoff for the Four-Month Safety Update Report adverse events that led to dropout in the open-label study P05898 (total N=321) were mostly psychiatric in nature aggression and suicidal ideation (3 patients each) and anxiety ADHD bipolar disorder depression depressive symptom irritability and suicidal behavior (2 patients each) Agitation anger exhibitionism mania panic attack and restlessness led to dropout in one patient each

27



Non-psychiatric adverse events that resulted in dropout in more than one patient in study P05898 were somnolencesedationhypersomnia (12 patients) and fatigue (4 patients) Non-psychiatric events that led to discontinuation in only one patient each were as follows akathisia dizziness dysgeusia dyskinesia dystonia narcolepsy drug ineffective accidental overdose intentional overdose glossodynia weight increased back pain and pregnancy

Table 7 Adverse Events Leading to Dropout (Trial P06107)

734 Significant Adverse Events

There are several significant adverse effects of asenapine and other atypical antipsychotics Observed effects in the placebo-controlled pediatric bipolar trial are discussed below

Metabolic Changes Hyperglycemia and Diabetes Mellitus

28



Mean changes from baseline to endpoint in fasting glucose levels in trial P06107 were higher in the asenapine groups

Placebo -22 mgdl (N=56) Asenapine 25mg +14 mgdl (N=51) Asenapine 5mg -05 mgdl (N=57) Asenapine 10mg +03 mgdl (N=52)

The proportions of patients who had a fasting glucose level ge126 mgdl at any point during trial P06107 were low across treatment groups


No patient in any treatment group had an HbA1c level ge70 at any time point

The fraction of patients with significant shifts from baseline in fasting glucose at any time during treatment are displayed in the following table A greater proportion of patients in each asenapine group had a shift in fasting glucose from the normal range to borderline high compared to placebo

Table 8 Proportion of Patients with Shifts in Fasting Glucose (Trial P06107)

Shift Placebo 25mg 5mg 10mg Normal to Low

(gt45 amp lt100) to le45 mgdl 0

(056) 0

(051) 0

(057) 0

(052) Normal to Borderline High

( gt45 amp lt100) to (ge100 amp lt126 mgdl) 4

(256) 6

(351) 5

(357) 8

(452) Normal to High

( gt45 amp lt100) to ge126 mgdl) 0

(056) 0

(051) 2

(157) 0

(052)

Adverse events in the hyperglycemianew onset diabetes mellitus broad SMQ category were reported in a higher proportion of asenapine patients compared to placebo


New onset metabolic syndrome (MBS) criteria were met by 0 (0101) of placebo patients and 4 (4104) 5 (599) and 2 (299) of patients in the asenapine 25mg 5mg and 10mg groups respectively Criteria defined by the International Diabetes

29



Federation require obesity (waist circumference ge90th percentile for children lt16 years old or for those 16 years and older ge94cm or ge84cm for European males and females respectively) ge2 specific lab abnormalities andor abnormal blood pressure measurements at the same visit

Patients with uncontrolled or unstable diabetes or a clinically significant abnormal blood glucose level were excluded from trial P06107

Dyslipidemia Mean changes from baseline to endpoint in lipid parameters in trial P06107 are displayed in the table below Asenapine patients at all doses tended to have increases in serum lipid levels compared to placebo patients

Table 9 Mean Change from Baseline to Endpoint in Lipid Measures (mgdl) (Trial P06107)

Placebo 25mg 5mg 10mg N Δ N Δ N Δ N Δ

Cholesterol 81 -36 89 +30 89 +62 86 +88 HDL 81 +02 88 +10 89 +17 86 +21 LDL 81 -35 89 -03 88 +15 85 +56

Fasting Triglycerides

57 -66 50 +87 57 +134 52 +147

The fraction of patients with significant shifts from baseline in lipid measurements during treatment are displayed in the following table A small number of asenapine patients had shifts in fasting triglycerides from the normal range to high values compared to no placebo patients

Table 10 Proportion of Patients with Significant Shifts in Lipid Parameters (Trial P06107)

Placebo 25mg 5mg 10mg Tot Cholesterol Normal to High

(lt170 to ge200 mgdl) 1

(181) 1

(189) 1

(189) 0

(086) HDL Normal to Low

(ge40 to lt40 mgdl) 4

(381) 3

(388) 2

(289) 6

(586) LDL Normal to High (lt130 to ge130 mgdl)

3 (281)

5 (489)

2 (288)

5 (485)

Fasting TGs Normal to High (lt150 to ge200 mgdl)

0 (057)

4 (250)

4 (257)

2 (152)

The proportion of patients with outlying values for cholesterol and triglyceride levels at any time during study drug treatment are shown in the table below A much larger

30



fraction of asenapine patients at all doses had outlying cholesterol and fasting triglyceride levels compared to placebo

Table 11 Proportion of Patients with Outlying Cholesterol or Triglyceride Levels (Trial P06107)

Placebo 25mg 5mg 10mg Total Cholesterol

(ge200 mgdl) 4

(381) 12

(1189) 12

(1189) 11

(986) Fasted Triglycerides

(ge200 mgdl) 2

(160) 8

(452) 8

(560) 9

(553)

Weight Gain Mean changes from baseline to endpoint in body weight in trial P06107 were

Placebo +05 kg (N=89) Asenapine 25mg +17 kg (N=92) Asenapine 5mg +16 kg (N=90) Asenapine 10mg +14 kg (N=87)

The percentages of subjects in this trial who experienced a 7 or greater increase in body weight from baseline to endpoint during the trial were much larger for each asenapine group versus placebo


Hypersensitivity Reactions In trial P06107 drug hypersensitivity adverse events were reported in four patients rash and pruritus each in one placebo patient chelitis in one asenapine 25mg patient and rash in one asenapine 5mg patient None were rated as serious and none led to dropout All were rated mild in severity

There was one serious case of drug hypersensitivity that occurred in the open-label study P05898 A 14 year old male (100212) experienced tongue swelling that was treated with oral diphenhydramine and resolved the same day He continued in the study at a reduced asenapine dose He had received placebo in the acute study P06107 and had received asenapine 10mg BID for 10 days in the open-label study prior to the event

Hyperprolactinemia Mean changes from baseline to endpoint in serum prolactin levels from trial P06107 reflected increases with the largest increase in the 10mg dose group

31



Placebo +25 ngml (N=72) Asenapine 25mg +32 ngml (N=82) Asenapine 5mg +21 ngml (N=84) Asenapine 10mg +64 ngml (N=77)

The proportions of patients who had an elevated prolactin level (geULN) at endpoint in trial P06107 were higher for asenapine than placebo


There were 2 patients in the 5mg group and one patient in the placebo group of this trial who had an adverse event potentially related to prolactin (dysmenorrhea) In addition one patient in the 10mg group experienced galactorrhea Thus the incidence rates of prolactin-related events were


Each event was rated as mild in severity None of these events were serious and none led to dropout

I searched the aexpt files of trial P06107 to locate reports of breast enlargement associated with asenapine The search terms were ldquogynecomastiardquo and ldquobreastrdquo with the objective of identifying adverse event occurrences with a preferred term (AEDECOD) or a verbatim term (AELIT) containing either of the search terms No such events were found

Seizures I searched the aexpt files of trials P06107 to locate reports of seizures associated with asenapine The search terms were ldquoseizrdquo and ldquoconvulsrdquo with the objective of identifying adverse event occurrences with a preferred term (AEDECOD) or a verbatim term (AELIT) containing either of the search terms No occurrences were located

Patients with any known or suspected seizure disorders were excluded from the trials

32



Somnolence The preferred terms somnolence sedation and hypersomnia were combined by the sponsor to gauge the incidence of adverse events related to somnolence in trial P05896 The reporting rates for the combined term by treatment group were


None of these events were classified as serious and most were rated as mild or moderate in severity Six patients dropped out because of one of these experiences (3 in the 25mg group one in the 5mg group and 2 in the 10mg group) Clearly somnolence was very common and related to asenapine treatment but infrequently led to dropout

Extrapyramidal Symptoms (EPS) The reporting rates for EPS-related events (based on SMQ broad definitions) in trial P06107 are shown in the table below

33



Table 12 Treatment-Emergent EPS-Related Adverse Events (Trial P05896)

Rates of Parkinson-like events and akathisias were higher in all asenapine dose groups compared to placebo but were not dose-related Dystonias and dyskinesias were not more frequent in asenapine versus placebo patients

The reporting rates of all non-akathisia EPS (broadly defined) were similar across treatment groups


Changes from baseline to endpoint in the Extrapyramidal Symptom Rating Scale (ESRS) III (dystonia) and IV (dyskinesia) scores in trial P06107 were comparable across treatment groups

34



Patients with a history of NMS tardive dyskinesia or tardive dystonia were excluded from the trials

Suicidal Ideation and Behavior Suicidal ideation and behavior was assessed during trial P06107 using the C-SSRS at each visit The percentage of patients who endorsed items on this scale are displayed in the table below In this table patients were enumerated only once in each cell However a patient who endorsed different items at different visits was counted in the cell for each item endorsed

Table 13 Number () of Patients with Positive Responses on the C-SSRS (Trial P06107)

About 90 of patients in each treatment group reported no events on the C-SSRS during the trial A higher proportion of patients in the 10mg group experienced suicidal ideation compared to placebo (8 vs 5) but this difference was not statistically significant (p= 04 2-tailed Fishers exact test) One patient in the placebo group and another in the 10mg group had active ideation with a method intent and plan There were no completed suicides in this trial There was one aborted attempt in the placebo group and one suicide attempt in the 10mg group Overall there was no clear evidence that asenapine treatment was causally associated with suicidal thoughts or behavior

35



Patients at imminent risk of self-harm suicidal ideation with intent in the prior 2 months or suicidal behavior in the prior 6 months were excluded from this trial

Depression Treatment-emergent depression was assessed in trial P06107 using the CDRS-R CDRS-R total scores were roughly comparable across treatment groups at baseline (range of 335 to 354) Mean changes from baseline at Day 21 reflected numeric improvement for the asenapine groups (especially the 5mg group) versus placebo

Placebo -61 (N=78) Asenapine 25mg -69 (N=87) Asenapine 5mg -87 (N=87) Asenapine 10mg -68 (N=81)

Likewise the percentages of CDRS-R responders (defined as a ge50 decrease from baseline in the total score) were greater for the asenapine-treated patients compared to placebo


These data suggest that asenapine treatment of pediatric patients with bipolar disorder in a manic or mixed state is not associated with an increase in depression

Oral Hypoesthesia Oral hypoesthesia is an event somewhat unique to asenapine caused by its anesthetic properties when administered sublingually In trial P06107 oral hypoesthesia was reported much more frequently in the asenapine treatment arms compared to placebo


None of these events were serious or led to dropout All were rated as mild or moderate in severity

Oral paresthesia and oral dysesthesia (such as a tingling sensation in the mouth) related adverse events were reported by several patients in this trial The percentages of patients who reported either oral hypoesthesia paresthesia or dysesthesia followed a similar pattern of reporting rates

36




Dysphagia There was one report of dysphagia in trial P06107 that occurred in the asenapine 25mg group (1 or 1104) The adverse event dataset (aexpt) for this trial was searched for reports of choking by searching all verbatim terms (AELIT) for any that contained any of the following ldquochokrdquo ldquoaspirationrdquo or ldquogagrdquo No such adverse events were identified

735 Submission Specific Primary Safety Concerns

The assessment of the potential effects of asenapine on learning and memory in pediatric patients with bipolar disorder consisted of the following tests in trial P06107

bull Color Word Interference Task (CWIT) - words describing a color are presented in colored font under one of two conditions in the congruent condition (in which the color word and the color of the word are the same eg the word red is printed in red color) and the incongruent condition (in which the color word and the color of the word are different) Performance is measured by response latencies that is lower numbers represent better performance Interference in the incongruent condition typically yields longer latencies than for the congruent condition Thus performance is assessed by the key metric ldquonet scorerdquo which equals incongruent latency minus congruent latency Latency of response is impacted by the speedaccuracy trade-off employed by each participant bull Letter Fluency Test (LFT) - a measure of language and executive function such as planning and strategic thinking The key measure is the ldquonumber of correct wordsrdquo with higher numbers representing better performance bull Semantic Fluency Test (SFT) - this is also a measure of language and executive function such as planning and strategic thinking The key measure is the ldquonumber of correct wordsrdquo with higher numbers representing better performance bull Auditory Number Sequencing (ANS) - a measure of working memory The key metric is the ldquonumber correctrdquo Higher number reflect better performance bull Strategic Target Detection Test (STDT) - a visual search task that indexes attention span Accuracy is intended to reflect interference with attention especially by performance at the four shape level The key metric is ldquototal correctrdquo with higher numbers reflecting better performance (total correct at the four shape level is taken as the key metric)

These assessments were added to the conduct of trial P06107 with a protocol amendment which was implemented more than a year after enrollment started Thus

37



the sample size for cognitive data is much smaller than the total number of randomized patients in this trial

Results on the key metrics are summarized in the following table The mean changes from baseline to endpoint generally reflected improvement with differences among treatment groups not felt to be clinically significant

Table 14 Summary of Results of Cognitive Testing (Trial P06107) Mean Change from Baseline to Endpoint in Key Metrics

TestUnits Placebo 25mg 5mg 10mg N Mean Δ N Mean Δ N Mean Δ N Mean Δ

CWIT (msec) 17 +485 9 -195 19 -710 17 +243 LFT

( correct) 34 +17 27 +15 28 +06 32 +10

SFT ( correct)

33 +07 28 +23 25 +08 30 -16

ANS ( correct)

33 +04 28 +13 27 -02 31 +06

STDT (total correct)

26 +39 24 -16 28 +45 27 +04

74 Supportive Safety Results

741 Common Adverse Events

The incidence of treatment-emergent adverse events in trial P06107 that were reported in at least one of the three asenapine arms at a rate ge2 (before rounding) and at a rate that was higher than the placebo rate are displayed in the table below

38



Table 15 Reporting Rates () of Adverse Reactions (Trial P06107) System Organ Class

AE Preferred Term Placebo 25mg 5mg 10mg N=101 N=104 N=99 N=99

Cardiac Disorders Tachycardia1 0 3 0 1

Gastrointestinal Disorders Oral paraesthesia2 4 25 25 30 Nausea 3 6 6 6 Abdominal pain3 7 9 3 5 Glossodynia 0 0 2 0

General Disorders and Administrative Site Disorders Fatigue4 5 4 8 14 Irritability 1 1 1 2

Immune System Disorders Seasonal allergy 0 0 1 2

Injury Poisoning and Procedural Complications Muscle strain 0 0 0 2

Investigations Weight increased 0 6 2 2 Hyperinsulinemia5 0 1 3 1 ALT increased 0 0 0 2 AST increased 0 0 0 2

Metabolism and Nutrition Disorders Increased appetite 2 10 9 6 Dehydration 1 0 2 0

Musculoskeletal and Connective Tissue Disorders Myalgia 0 0 2 1

Nervous System Disorders Somnolence6 12 46 53 49 Headache 6 8 11 9 Dizziness 3 6 10 5 Dysgeusia 2 4 5 9 Akathisia 0 2 2 1 Parkinsonism 0 1 0 2

Psychiatric Disorders

1 Includes the preferred terms tachycardia and heart rate increased 2 Includes the preferred terms oral hypoesthesia oral paresthesia and oral dysesthesia 3 Includes the preferred terms abdominal pain abdominal pain upper abdominal pain lower and abdominal discomfort 4 Includes the preferred terms fatigue and lethargy 5 Includes the preferred terms hyperinsulinemia and blood insulin increased 6 Includes the preferred terms somnolence sedation and hypersomnia

39





Insomnia 3 3 4 3 Suicidal ideation 1 4 1 3 Bipolar Disorder7 4 0 5 4 Anger 0 0 0 2

Reproductive System and Breast Disorders Dysmenorrhea 1 0 2 0

Respiratory Thoracic and Mediastinal Disorders Oropharyngeal pain 2 0 3 1 Nasal congestion 1 0 2 0 Dyspnea 0 0 2 0

Skin and Subcutaneous Tissue Disorders Rash 1 0 1 2

Common probably drug-related adverse reactions (reported by at least 5 of patients in at least one asenapine arm and at a rate at least twice the placebo rate) were oral paresthesia nausea fatigue weight increased increased appetite somnolence dizziness and dysgeusia

742 Laboratory Findings

Hematology In trial P06107 mean changes from baseline to endpoint in hematology parameters were similar across treatment groups except for platelet counts for which there was a trend for increases with increasing asenapine dose

Placebo +15 x103μL (N=79) Asenapine 25mg +44 x103μL (N=85)Asenapine 5mg +87 x103μL (N=86)Asenapine 10mg +135 x103μL (N=84)

Median changes in platelet count were larger in the asenapine groups (+8 to +10 x103μL) compared to placebo (-10 x103μL)

The proportions of patients who met Predefined Limits of Change (PDLC) for hematology measures in trial P06107 are presented in the table below

7 Includes the preferred terms bipolar disorder bipolar I disorder mania mood swings and tachyphrenia

40



Table 16 Percentage of Patients With Hematology Values That Met PDLC During Treatment (Trial P06107)

41



The proportion of PLDC outliers for indices of low white blood cell (WBC) counts was larger for asenapine than placebo for the following measures

bull leukocyte count le08 xLLN bull mild reduction in neutrophil count le1500μL

One patient a 14 year old Black female in the asenapine 25mg group (100422) had severe neutropenia (ie a neutrophil count le500μL) on Day 21 of trial P06107 Despite this finding this patient continued treatment in study P05898 on Day 27 of this study her neutrophil count improved and on Day 131 returned to baseline Her WBC and neutrophil counts are summarized below

WBC (total) Neutrophil Count Screening 3600μL 1400μL Trial P06107 Baseline 3300μL 1200μL Day 21 3100μL 400μL Study P05898 Day 27 2800μL 900μL Day 131 3800μL 1600μL

This patient experienced a possible urinary tract infection with proteinuria that was detected on Day 1 of trial P06107 and reportedly ended on Day 21 of that trial Otherwise no adverse events likely to be related to neutropenia were reported during either study

I searched the lab results dataset (labrsltxpt) for each of the two Phase 3 pediatric bipolar disorder trials for other patients who had significant leukopenia (le1000μL) or neutropenia (le500μL) at non-baseline visits The following cases were identified from this search

In the 50-week open-label bipolar disorder study P05898 (as of the interim safety cutoff date July 12 2013) a 16 year old male (100261) had severe neutropenia on Day 1778

Baseline 4300μLDay 28 3900μLDay 132 3500μLDay 177 400μL

This patient reportedly completed the trial without interruption of study medication No subsequent laboratory data was captured According to information from the sponsor submitted on February 3 2015 the patient was asymptomatic and continued to be

8 Complete safety datasets for study P05898 were not available at the time of this review

42



followed by the investigator for over 2 years after completing study P05898 During this time the investigator reports that the patient has been physically healthy

In trial P06107 the proportions of patients who had a treatment-emergent adverse event coded as either leukopenia neutropenia or ldquowhite blood cell count decreasedrdquo were small


No patient dropped out of trial P06107 because of an adverse event related to a hematology lab test abnormality

Chemistry Mean changes from baseline to endpoint in chemistry variables were comparable to placebo with the exception of the liver transaminases aspartate aminotransferase (AST) alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT) There were small increases relative to placebo in the 25mg and 5mg groups and larger increases in the 10mg group as shown in the table below

Table 17 Mean Change from Baseline to Endpoint in Liver Transaminase Concentrations (UL)

Placebo Asenapine 25mg Asenapine 5mg Asenapine 10mg N Δ N Δ N Δ N Δ

AST 80 -12 90 +06 90 +04 85 +34 ALT 80 -10 90 +13 90 +39 85 +88 GGT 80 -12 90 +04 90 +12 85 +22

Mean changes from baseline in alkaline phosphatase and total bilirubin were unremarkable

With respect to hormone parameters there were increases in serum prolactin levels in all groups including placebo with the largest mean change from baseline in the asenapine 10mg group

Placebo +25 μgL (N=72) Asenapine 25mg +33 μgL (N=82) Asenapine 5mg +21 μgL (N=84) Asenapine 10mg +64 μgL (N=77)

43



The proportions of patients who met Predefined Limits of Change (PDLC) for chemistry measures in trial P06107 are presented in the table below There were appreciable differences between asenapine and placebo for the following variables

bull BUN increased (all asenapine dose groups) bull phosphorus increased (all asenapine dose groups) bull ALT elevated (10mg) bull total bilirubin increased (25 and 5mg)

The increase in BUN is less concerning given 1) decreases from baseline to endpoint in mean serum creatinine for asenapine versus placebo and 2) an absence of asenapine patients meeting the PDLC criterion for elevated serum creatinine levels

The clinical relevance of the increased proportion of asenapine patients with elevated phosphorus levels is not clear

Two patients in trial P6107 met the PDLC criterion for SGPT One patient (100641) had a baseline SGPT of 30 UL an increase to 190 UL after about 3 weeks of asenapine in the 10mg group and a decrease to 78 UL 5 days after stopping drug

The other patient (101070) a 16 year old female had a baseline SGPT of 32 UL and an increase to 115 UL after 3 weeks of treatment in the asenapine 10mg group The AST also slightly increased (62 UL) These findings were attributed by the investigator to ibuprofen use which the patient had been taking prophylactically for pain and the dose of which was increased during the trial to treat headaches The patient was continued on asenapine in study P05898 and subsequent laboratory testing revealed a gradual return of both SGPT and SGOT levels to normal range over the next month

To further evaluate the findings regarding increased ALT and total bilirubin levels I searched the laboratory results datasets (labrsltxpt) for trials P06107 and P05898 (as of the interim safety cutoff date July 12 2013) to identify patients who met Hyrsquos Law criteria (ALT or AST ge3 xULN total bilirubin ge2 xULN and alkaline phosphatase lt2 xULN) I found no case that met these criteria

There were no dropouts in studies P06107 or P05898 because of adverse events related to chemistry laboratory abnormalities

44



Table 18 Percentage of Patients With Chemistry Values That Met PDLC During Treatment (Trial P06107)

45



Table 18 Percentage of Patients With Chemistry Values That Met PDLC During Treatment (continued)

46




47



Urinalysis Mean changes from baseline to endpoint in urine specific gravity and urine pH were small in all treatment groups in trial P06107

The proportion of asenapine patients meeting PDLC criteria for any urinalysis parameter was higher than that in the placebo group for only glucosuria (non-negative finding) in the 5mg group


The difference between placebo and the 5mg group was not statistically significant (p =050 2-tailed Fishers exact test)

No patient in this trial dropped out because of an adverse event related to a urinalysis abnormality

743 Vital Signs

Mean changes from baseline to endpoint in supine and standing systolic and diastolic blood pressure and pulse in trial P06107 are shown in the table below

Appreciable differences between asenapine and placebo are present for the following measures

bull increased standing DBP (about 2 mmHg across all asenapine doses) bull increased supine pulse (2-4 bpm across all asenapine doses)

The mean increase in supine pulse relative to placebo was especially noticeable in the 10mg dose group (+43 bpm) The median changes were +45 bpm for asenapine 10mg versus 00 bpm for placebo

48



Table 19 Mean Changes From Baseline To Endpoint in Blood Pressure and Pulse (Trial P06107)

49



Mean changes in standing diastolic blood pressure over time adjusted for placebo were not substantially different across dose groups and tended to be largest at the final visit (an increase of about 3 mmHg on Day 21) as shown in the following table

Table 20 Placebo-Adjusted Changes From Baseline in Standing Diastolic Blood Pressure (mmHg) By Visit (Trial P06107)

Visit 25mg 5mg 10mg Day 4 +16 +23 +19 Day 7 +19 +25 +18

Day 14 +09 +21 +23 Day 21 +34 +31 +27

Examination of the mean changes in supine pulse relative to placebo by visit reveals that in all dose groups increases relative to placebo began in the first few days of treatment but did not persist in the two lower dose groups Increases were greater in the 10mg dose group as shown in the table below

Table 21 Placebo-Adjusted Changes From Baseline in Supine Pulse (bpm) By Visit (Trial P06107)


Day 14 +21 +28 +64 Day 21 +19 +10 +21

In sum vital sign changes associated with asenapine treatment were increases in supine pulse (2-3 bpm in the 25mg and 5mg groups and 4-6 bpm in the 10mg group after adjustment for the placebo change) and increases in standing diastolic blood pressure of 2-3 mmHg in all asenapine dose groups compared to placebo

PDLC criteria for vital signs are displayed in the table below

50



Table 22 Pre-Defined Limits of Change Criteria for Vital Signs

The proportions of patients who met any of these criteria during trial P06107 are presented in the following table

51



Table 23 Percentage of Patients With Vital Sign Measurements That Met PDLC During Treatment (Trial P06107)

Differences between asenapine and placebo were noted for the following measures

bull low supine DBP (25mg and 10mg) bull high standing DBP (all asenapine dose groups) bull high standing pulse (5mg and 10mg)

These data exhibit considerable variability across dose groups and among related variables The larger proportions of asenapine patients with high standing diastolic blood pressure compared to placebo is consistent with the higher mean changes in this variable noted above Nonetheless these differences in the proportions meeting PDLC criteria from placebo were not statistically significant (alpha=010)

Orthostatic hypotension was defined as gt20 mmHg drop in systolic blood pressure or gt10 mmHg drop in diastolic blood pressure (with a change in position from supine to standing) at any visit The percentages of patients who met this criterion in trial P06107 are presented below (denominators represent only those patients with both supine and standing measurements taken in the order supine to standing with le3 minutes between positions)

52




The frequency of orthostatic hypotension was comparable across all treatment groups

There were two cases of treatment-emergent syncope in trial P06107 both on asenapine

bull one patient was a 12 year old female (101263) in the 25mg group who experienced syncope immediately after visiting a family member in the intensive care unit of a hospital She was reportedly emotionally upset by the visit and had a history of fainting under emotionally disturbing circumstances The episode lasted several minutes She was taken to the emergency room of the hospital given intravenous fluids and discharged to home She was discontinued from the study because of non-compliance having taken her last dose of asenapine the day prior to the syncopal episode bull the other patient was a 12 year old female (100821) in the 5mg group who fainted during attempted venipuncture at the study site She quickly regained consciousness and completed the trial

A causal link to asenapine seems unlikely in both cases

There were no dropouts in trial P06107 because of a vital sign abnormality

744 Electrocardiograms (ECGs)

Mean changes from baseline to endpoint in ECG measures for patients in trial P06107 are displayed in the following table

The only remarkable differences relative to placebo were increases in heart rate (about 3 bpm in the 10mg group) consistent with the vital sign changes described above and decreases in the RR interval corresponding to the increases in heart rate

The increases in QTcB relative to placebo (about +4 msec in the 25mg group and +3 msec in the 10mg group) are not considered clinically significant and are greater than the changes in QTcF (+18 msec in the 25mg group and 00 msec in the 10mg group)

53



Table 24 Changes From Baseline To Endpoint in ECG Parameters (Trial P06107)

54



Table 24 Changes From Baseline To Endpoint in ECG Parameters (continued)

55



The criteria for PDLC for ECG measures in trial P06107 are provided in the table below

Table 25 Pre-Defined Limits of Change for ECG Parameters

The proportion of patients who met any of these criteria during treatment in trial P06107 are shown in the following table The only remarkable finding from these data are increased proportions of asenapine patients compared to placebo with a change in QTcB ge30msec However the decreasing frequency of this finding with increasing dose (inverse dose-response) which was also observed for the proportions of patients with a change in QTcF ge30msec casts doubt on whether this is attributable to asenapine exposure

No patient in any treatment group had a QTcB or QTcF value of 500 msec or greater

56



Table 26 Proportion of Patients With PDLC Changes in ECG Parameters (Trial P06107)

There were no dropouts in trial P06107 because of an adverse event related to an ECG abnormality

There were 2 events within the torsades de pointeQT prolongation broad SMQ in this trial Both were reports of syncope and are discussed under section 743 above

57



75 Other Safety Explorations

751 Dose Dependency for Adverse Events

Among the common and probably drug-related adverse reactions in trial P06107 (somnolence fatigue dizziness oral paresthesia nausea weight increased increased appetite and dysgeusia) only fatigue and dysgeusia showed some evidence of being dose-related

25mg 5mg 10mg Fatigue 4 8 14 Dysgeusia 4 5 9

753 Drug-Demographic Interactions

The sponsor conducted analyses of the effect of gender and race for treatment-emergent adverse events by MedDRA preferred terms in trial P06107 that were reported by at least 5 of asenapine-treated patients in a demographicdose subgroup and at a rate at least twice the corresponding placebo rate Statistical testing of the odds ratios using the Breslow-Day test was conducted using a nominal alpha level of 010

Significant differences with respect to gender were observed for sedation in the 25mg and 5mg groups Significant differences by racial subgroup were seen for increased appetite in the 25mg and 5mg groups and for oral paresthesia in the 10mg group These findings are summarized in the following table

For sedation in the 10mg group versus placebo the odds ratios for the gender subgroups followed the pattern for the lower groups (ie much larger OR in females) and approached the nominal significance level (p= 0119) But for all three dose groups the asenapine rates were comparable for females and males the significant differences being explained by a large difference in the placebo rate (much larger in males) The reason for placebo-treated males to report sedation much more commonly than females is not known

The differences regarding increased appetite by racial subgroups cannot be so consistently explained For example in the Black subgroup the odds ratio in the 25mg group is 18 but in the 5mg group it is 04 (more common in placebo) and in the 10mg group it is 18 again Likewise the odds ratios in the White subgroup are much higher in the two lower dose groups than in the high dose group Such inconsistencies across dose groups are difficult to explain and suggest that this may be a spurious finding

58



Similarly inconsistent odds ratios across the three dose groups for oral paresthesia particularly within the Black and Others subgroups make it hard to draw a firm conclusion regarding an effect of race on the incidence of this adverse event

Table 27 Treatment-Emergent Adverse Event Incidence () By Demographic Subgroups (Trial P06107)

Sedation Subgroup Placebo 25mg Odds Ratio p-Value Female 2 17 130 0051

Male 11 14 13 Sedation Subgroup Placebo 5mg Odds Ratio p-Value

Female 2 21 169 0044 Male 11 16 17

Increased Appetite

Subgroup Placebo 25mg Odds Ratio p-Value White 0 9 150 0089 Black 9 14 18 Others 0 0 NA

Increased Appetite


Oral Paresthesia Subgroup Placebo 10mg Odds Ratio p-Value White 0 11 176 0006 Black 4 0 03 Others 10 57 120

76 Additional Safety Evaluations

762 Human Reproduction and Pregnancy Data

There was one pregnancy in trial P06107 A 16 year old female (100488) in the asenapine 10mg group had a positive serum pregnancy test on Day 21 of the trial (screening and baseline pregnancy tests were negative) This patient had a miscarriage during the safety follow-up period (Day 42)

Two pregnancies occurred during the 50-week open-label extension trial (P05898) as of October 31 2014

bull a 15 year old female (100484) taking asenapine 10mg BID had positive urine and serum pregnancy tests on Day 29 of the study The outcome of the pregnancy is unknown

59



bull a 17 year old female (100803) had a positive serum pregnancy test on Day 30 of the study The patient stopped the study drug (asenapine 10mg BID) The pregnancy was terminated about 2 weeks later

No other new data on the reproductive effects of asenapine are presented in this supplement

763 Pediatrics and Assessment of Effects on Growth

Age- and sex-adjusted growth percentile rankings were determined for patients in trial P06107 At baseline mean percentiles indicated that the patient sample was of roughly average height (mean percentiles 46-53) Changes from baseline to endpoint in height percentile ranking among all treatment groups were small (lt1) and asenapine patients tended to fall slightly behind the placebo group

Placebo +053 (N=89) Asenapine 25mg +003 (N=92) Asenapine 5mg -008 (N=90) Asenapine 10mg -033 (N=87)

In terms of z-score changes from baseline to endpoint for height there was not much difference among the groups

Placebo +002 SD (N=89) Asenapine 25mg -000 SD (N=92) Asenapine 5mg -001 SD (N=90) Asenapine 10mg -001 SD (N=87)

In the 50-week open-label bipolar disorder study P05898 (as of the interim safety cutoff date July 12 2013) the changes from the baseline for this study in percentile rankings and z-scores for height (based on all patients treated with placebo in the preceding short-term trial) were +027 (N=65) and -000 SD (N=65)

To evaluate the potential effects of asenapine on sexual maturation Tanner staging in patients of both sexes was performed Tanner staging consisted of breast staging for females genital growth staging for males and pubic hair staging for females and males Shifts from baseline to endpoint in Tanner stage are displayed for females and males in the following two tables

Among females there were relatively small numbers of asenapine-treated patients who experienced a negative change in Tanner stage across all dose groups compared to no placebo patients with a negative change On the other hand a number of asenapine patients had an increase of at least one stage comparable to or greater than the number of such placebo patients

60



For males over 90 in each treatment group had no change in Tanner stage One patient had a negative change for each measure and a small number had an increase of one level or greater

Given the brief duration of this trial and missing data for a number of patients it is difficult to make a precise assessment of the effect of asenapine on sexual maturation

Table 28 Shifts in Tanner Stage Among Females (Trial P06107)

61



Table 29 Shifts in Tanner Stage Among Males (Trial P06107)

Among placeboasenapine patients in the long-term study P05898 (as of the interim cutoff date) shifts in Tanner stage from baseline to endpoint are displayed in the following table An appreciable number of males and females progressed in Tanner stage during this study but these figures cannot be interpreted without a control group

Table 30 Enumeration of Patients (N()) with Tanner Stage Shifts Study P05898 (PlaceboAsenapine-Treated Patients)

Sex Stage Shift Genital GrowthBreast Pubic Hair Males (M=14)

0 10 (71) 10 (71) +1 3 (21) 3 (21) +2 1 (7) 1 (7)

Females (N=20)

Negative 0 1 (5) 0 14 (70) 13 (65)

+1 6 (30) 5 (25) +3 0 1 (5)

62



764 Overdose Drug Abuse Potential Withdrawal and Rebound

One patient (101081) in the placebo group of trial P06107 took an accidental overdose of study medication 2 placebo tablets BID (instead of one tablet BID) for 4 consecutive days Another patient (100981) in the 10mg group took an overdose of acetaminophen (20 extra strength tablets) in a suicide attempt Two patients in the 50shyweek open label study P05898 took overdoses classified as serious adverse events as of October 31 2014 one (100202) took an accidental overdose of Ambien and the other (100602) took an intentional overdose of melatonin Both had been treated with asenapine in the preceding short-term trial

There were no studies to assess drug abuse potential rebound or withdrawal in pediatric patients with bipolar I disorder

Patients with a history of substance abuse or dependence (except nicotine and caffeine) within the previous 6 months were excluded from the bipolar disorder studies

8 Postmarket Experience The sponsor provided an assessment of postmarketing exposure and safety in pediatric patients ages 10-17 years According to distribution data from US drug stores indicates that of all prescribed doses were for patients ages 10-17 years If this is extrapolated to worldwide exposure exposure to asenapine in this age range would be patient-years from August 13 2009 through October 31 2013 The Four-Month Safety Update Report provides data for the interval from November 1 2013 to October 31 2014 During this timeframe it is estimated there was

patient-years of exposure in the 10 to 17 year age range

(b) (4)

(b) (4)

(b) (4)

(b) (4)

Merck searched their safety database (MARRS) for all spontaneous and literature reports where asenapine was used in patients 10-17 years from product launch (October 2009) to October 31 2013 A total of 100 postmarketing safety reports had been received that involved 342 events No events were fatal The sponsorrsquos examination of the events revealed that 44 were unlisted in the current labeling Of these 19 contained insufficient information for analysis and 17 represented events closely related or the consequence of labeled events Of the remaining 8 cases I found that the only remarkable event was oropharyngeal blistering in a 13 year old female patient who had a positive dechallenge after stopping asenapine This event is labeled as a postmarketing report The most common event reported was oral hypoesthesia (19 cases1000 patient-years) This event is labeled

My own examination of the listing of these 342 adverse events revealed that none represented a previously unrecognized hazard associated with asenapine treatment

63



The Four-Month Safety Update Report contains an updated search covering the period from November 1 2013 to October 31 2014 During this time 13

(b) (4)

postmarketing safety reports describing 43 adverse events in patients in the age range 10 to 17 years were received No case had a fatal outcome Three reports were prompted by events consistent with lack of efficacy two described medication errors prescribed overdoses or off-label use and five were for adverse events either labeled or related to labeled reactions The other three cases are summarized below

bull a 14 year old male experienced non-food vomiting mouth foaming white tongue and mild cyanosis the day he started asenapine 10mg qday for a ldquomanic state in congenital dementiardquo Asenapine was stopped the next day and he recovered that same day Concomitant medications were fluoxetine quetiapine clothiapine bull a 14 year old female experienced pain under the rib cage and shortness of breath within 3 months of starting asenapine 5mg qhs for schizophrenia She was medically evaluated and no treatment was administered Other events included tongue numbness (date unknown) and a ruptured ovarian cyst with vasovagal reaction (about 3 years after starting asenapine) She recovered from the latter events and asenapine was stopped At some time after discontinuation she had multiple episodes of dizziness pain behind her head chest discomfort and trouble breathing These events resolved 2 months later bull an adolescent female (age not specified) started asenapine 25mg for 2-3 days to treat borderline personality disorder On an unknown date she experienced projectile vomiting nausea and lack of appetite Asenapine was stopped and not restarted The outcome of the events was reported as resolved The physician suspected a problem with the batch of drug

I examined the listing of these 43 adverse events and found that none represented a previously unrecognized hazard likely to be caused by asenapine treatment

Overall the sponsor concluded that the postmarketing safety data for patients age 10shy17 years was consistent with the US labeling

9 Appendices

91 Literature ReviewReferences

Merck staff reviewed the published literature from January 1 2009 through October 31 2013 and provided the search results in the original submission of this application The Clinical Literature Information Center (CLIC) is located within Merck Research Laboratories Information Technology division and maintains a database of abstracts of published literature related to Merck products This database encompasses over 400000 CLIC-authored abstracts as well as author abstracts These abstracts were searched by the CLIC screening staff using the terms ldquoasenapinerdquo ldquopediatricrdquo ldquocase reportsrdquo and ldquopublished articlesrdquo to identify relevant abstracts Full articles were

64



requested when abstracts of interest were found Ronald Landbloom MD the Clinical Director of Neuroscience at Merck provided a signed warrant on January 21 2015 that he evaluated the results of this literature search and confirmed that there were no unexpected safety findings with asenapine use in pediatrics

The Four-Month Safety Update Report contained an updated literature review covering the interval from November 1 2013 to October 31 2014 This search was conducted using MedLine Embase and Biosis using the search string ldquo(asenapine OR saphris) AND (human) AND (20131101-20141031) AND (pediatric or child or adolescent)rdquo

conducted the search at the abstract level Darren Weissman MD the Director of

(b) (4)

Pharmacovigilance and Risk Management at Forest Research Institute provided a signed warrant on January 20 2015 that he evaluated the results of this literature search and confirmed that there were no unexpected safety findings with asenapine use in pediatrics found in the literature

92 Labeling Recommendations

Adverse reaction information in Section 6 of Saphris labeling should be revised to describe the reporting rates of combined event terms ie terms which encompass a number of closely related preferred terms as discussed in section 712 above

93 Advisory Committee Meeting

This supplement was not taken to an Advisory Committee

65


---------------------------------------------------------------------------------------------------------

---------------------------------------------------------------------------------------------------------

----------------------------------------------------

This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature

s

GREGORY M DUBITSKY 02172015

JING ZHANG 02182015



Table of Contents

1 RECOMMENDATIONSRISK BENEFIT ASSESSMENT 4

11 Recommendation on Regulatory Action 4 12 Risk Benefit Assessment 4 13 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies 4 14 Recommendations for Postmarket Requirements and Commitments 4

2 INTRODUCTION AND REGULATORY BACKGROUND 4

21 Product Information 4 22 Tables of Currently Available Treatments for Proposed Indications 4 23 Availability of Proposed Active Ingredient in the United States 5 24 Important Safety Issues With Consideration to Related Drugs 5 25 Summary of Presubmission Regulatory Activity Related to Submission 5 26 Other Relevant Background Information 6

3 ETHICS AND GOOD CLINICAL PRACTICES 6

31 Submission Quality and Integrity 6 32 Compliance with Good Clinical Practices 7 33 Financial Disclosures 7

4 SIGNIFICANT EFFICACYSAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES 9

44 Clinical Pharmacology 9 441 Mechanism of Action 9 442 Pharmacodynamics 9 443 Pharmacokinetics 9

5 SOURCES OF CLINICAL DATA 10

51 Tables of StudiesClinical Trials 10 52 Review Strategy 11

6 REVIEW OF EFFICACY 11

Efficacy Summary 11 61 Efficacy in Pediatric Schizophrenia 11

611 Methods 11 612 Demographics 13 613 Subject Disposition 13 614 Analysis of the Primary Endpoint 14 615 Analysis of the Key Secondary Endpoints 15 616 Other Endpoints 16 617 Subpopulations 17 618 Analysis of Clinical Information Relevant to Dosing Recommendations 20 619 Discussion of Persistence of Efficacy andor Tolerance of Effects 20

2















9 APPENDICES 64


3

















4
















5













6














Product Saphris





7



















8















9




















10



52 Review Strategy





611 Methods





11








12





612 Demographics





13









14







15





616 Other Endpoints





16




617 Subpopulations


17




18




19









(b) (4)

20











22



71 Methods










decreased





23











24




Age (years)







25







731 Deaths




26












27








28












(056) 0

(051) 0

(057) 0



(256) 6

(351) 5

(357) 8



(056) 0

(051) 2

(157) 0

(052)




29










57 -66 50 +87 57 +134 52 +147





(181) 1

(189) 1

(189) 0



(381) 3

(388) 2

(289) 6


3 (281)

5 (489)

2 (288)

5 (485)


0 (057)

4 (250)

4 (257)

2 (152)


30






(ge200 mgdl) 4

(381) 12

(1189) 12

(1189) 11


(ge200 mgdl) 2

(160) 8

(452) 8

(560) 9

(553)








31












32







33








34







35













36









37







CWIT (msec) 17 +485 9 -195 19 -710 17 +243 LFT

( correct) 34 +17 27 +15 28 +06 32 +10

SFT ( correct)

33 +07 28 +23 25 +08 30 -16

ANS ( correct)

33 +04 28 +13 27 -02 31 +06


26 +39 24 -16 28 +45 27 +04




38
















39
















40




41













42










AST 80 -12 90 +06 90 +04 85 +34 ALT 80 -10 90 +13 90 +39 85 +88 GGT 80 -12 90 +04 90 +12 85 +22




43











44




45




46




47








743 Vital Signs





48




49






Day 14 +09 +21 +23 Day 21 +34 +31 +27




Day 14 +21 +28 +64 Day 21 +19 +10 +21



50





51








52













53




54




55







56






57












58







Female 2 21 169 0044 Male 11 16 17

Increased Appetite


Increased Appetite








59













60






61







0 10 (71) 10 (71) +1 3 (21) 3 (21) +2 1 (7) 1 (7)

Females (N=20)

Negative 0 1 (5) 0 14 (70) 13 (65)

+1 6 (30) 5 (25) +3 0 1 (5)

62









(b) (4)

(b) (4)

(b) (4)

(b) (4)



63




(b) (4)





9 Appendices



64






(b) (4)






65


---------------------------------------------------------------------------------------------------------

---------------------------------------------------------------------------------------------------------

----------------------------------------------------


s


JING ZHANG 02182015















9 APPENDICES 64


3

















4
















5













6














Product Saphris





7



















8















9




















10



52 Review Strategy





611 Methods





11








12





612 Demographics





13









14







15





616 Other Endpoints





16




617 Subpopulations


17




18




19









(b) (4)

20











22



71 Methods










decreased





23











24




Age (years)







25







731 Deaths




26












27








28












(056) 0

(051) 0

(057) 0



(256) 6

(351) 5

(357) 8



(056) 0

(051) 2

(157) 0

(052)




29










57 -66 50 +87 57 +134 52 +147





(181) 1

(189) 1

(189) 0



(381) 3

(388) 2

(289) 6


3 (281)

5 (489)

2 (288)

5 (485)


0 (057)

4 (250)

4 (257)

2 (152)


30






(ge200 mgdl) 4

(381) 12

(1189) 12

(1189) 11


(ge200 mgdl) 2

(160) 8

(452) 8

(560) 9

(553)








31












32







33








34







35













36









37







CWIT (msec) 17 +485 9 -195 19 -710 17 +243 LFT

( correct) 34 +17 27 +15 28 +06 32 +10

SFT ( correct)

33 +07 28 +23 25 +08 30 -16

ANS ( correct)

33 +04 28 +13 27 -02 31 +06


26 +39 24 -16 28 +45 27 +04




38
















39
















40




41













42










AST 80 -12 90 +06 90 +04 85 +34 ALT 80 -10 90 +13 90 +39 85 +88 GGT 80 -12 90 +04 90 +12 85 +22




43











44




45




46




47








743 Vital Signs





48




49






Day 14 +09 +21 +23 Day 21 +34 +31 +27




Day 14 +21 +28 +64 Day 21 +19 +10 +21



50





51








52













53




54




55







56






57












58







Female 2 21 169 0044 Male 11 16 17

Increased Appetite


Increased Appetite








59













60






61







0 10 (71) 10 (71) +1 3 (21) 3 (21) +2 1 (7) 1 (7)

Females (N=20)

Negative 0 1 (5) 0 14 (70) 13 (65)

+1 6 (30) 5 (25) +3 0 1 (5)

62









(b) (4)

(b) (4)

(b) (4)

(b) (4)



63




(b) (4)





9 Appendices



64






(b) (4)






65


---------------------------------------------------------------------------------------------------------

---------------------------------------------------------------------------------------------------------

----------------------------------------------------


s


JING ZHANG 02182015

















4
















5













6














Product Saphris





7



















8















9




















10



52 Review Strategy





611 Methods





11








12





612 Demographics





13









14







15





616 Other Endpoints





16




617 Subpopulations


17




18




19









(b) (4)

20











22



71 Methods










decreased





23











24




Age (years)







25







731 Deaths




26












27








28












(056) 0

(051) 0

(057) 0



(256) 6

(351) 5

(357) 8



(056) 0

(051) 2

(157) 0

(052)




29










57 -66 50 +87 57 +134 52 +147





(181) 1

(189) 1

(189) 0



(381) 3

(388) 2

(289) 6


3 (281)

5 (489)

2 (288)

5 (485)


0 (057)

4 (250)

4 (257)

2 (152)


30






(ge200 mgdl) 4

(381) 12

(1189) 12

(1189) 11


(ge200 mgdl) 2

(160) 8

(452) 8

(560) 9

(553)








31












32







33








34







35













36









37







CWIT (msec) 17 +485 9 -195 19 -710 17 +243 LFT

( correct) 34 +17 27 +15 28 +06 32 +10

SFT ( correct)

33 +07 28 +23 25 +08 30 -16

ANS ( correct)

33 +04 28 +13 27 -02 31 +06


26 +39 24 -16 28 +45 27 +04




38
















39
















40




41













42










AST 80 -12 90 +06 90 +04 85 +34 ALT 80 -10 90 +13 90 +39 85 +88 GGT 80 -12 90 +04 90 +12 85 +22




43











44




45




46




47








743 Vital Signs





48




49






Day 14 +09 +21 +23 Day 21 +34 +31 +27




Day 14 +21 +28 +64 Day 21 +19 +10 +21



50





51








52













53




54




55







56






57












58







Female 2 21 169 0044 Male 11 16 17

Increased Appetite


Increased Appetite








59













60






61







0 10 (71) 10 (71) +1 3 (21) 3 (21) +2 1 (7) 1 (7)

Females (N=20)

Negative 0 1 (5) 0 14 (70) 13 (65)

+1 6 (30) 5 (25) +3 0 1 (5)

62









(b) (4)

(b) (4)

(b) (4)

(b) (4)



63




(b) (4)





9 Appendices



64






(b) (4)






65


---------------------------------------------------------------------------------------------------------

---------------------------------------------------------------------------------------------------------

----------------------------------------------------


s


JING ZHANG 02182015
















5













6














Product Saphris





7



















8















9




















10



52 Review Strategy





611 Methods





11








12





612 Demographics





13









14







15





616 Other Endpoints





16




617 Subpopulations


17




18




19









(b) (4)

20











22



71 Methods










decreased





23











24




Age (years)







25







731 Deaths




26












27








28












(056) 0

(051) 0

(057) 0



(256) 6

(351) 5

(357) 8



(056) 0

(051) 2

(157) 0

(052)




29










57 -66 50 +87 57 +134 52 +147





(181) 1

(189) 1

(189) 0



(381) 3

(388) 2

(289) 6


3 (281)

5 (489)

2 (288)

5 (485)


0 (057)

4 (250)

4 (257)

2 (152)


30






(ge200 mgdl) 4

(381) 12

(1189) 12

(1189) 11


(ge200 mgdl) 2

(160) 8

(452) 8

(560) 9

(553)








31












32







33








34







35













36









37







CWIT (msec) 17 +485 9 -195 19 -710 17 +243 LFT

( correct) 34 +17 27 +15 28 +06 32 +10

SFT ( correct)

33 +07 28 +23 25 +08 30 -16

ANS ( correct)

33 +04 28 +13 27 -02 31 +06


26 +39 24 -16 28 +45 27 +04




38
















39
















40




41













42










AST 80 -12 90 +06 90 +04 85 +34 ALT 80 -10 90 +13 90 +39 85 +88 GGT 80 -12 90 +04 90 +12 85 +22




43











44




45




46




47








743 Vital Signs





48




49






Day 14 +09 +21 +23 Day 21 +34 +31 +27




Day 14 +21 +28 +64 Day 21 +19 +10 +21



50





51








52













53




54




55







56






57












58







Female 2 21 169 0044 Male 11 16 17

Increased Appetite


Increased Appetite








59













60






61







0 10 (71) 10 (71) +1 3 (21) 3 (21) +2 1 (7) 1 (7)

Females (N=20)

Negative 0 1 (5) 0 14 (70) 13 (65)

+1 6 (30) 5 (25) +3 0 1 (5)

62









(b) (4)

(b) (4)

(b) (4)

(b) (4)



63




(b) (4)





9 Appendices



64






(b) (4)






65


---------------------------------------------------------------------------------------------------------

---------------------------------------------------------------------------------------------------------

----------------------------------------------------


s


JING ZHANG 02182015













6














Product Saphris





7



















8















9




















10



52 Review Strategy





611 Methods





11








12





612 Demographics





13









14







15





616 Other Endpoints





16




617 Subpopulations


17




18




19









(b) (4)

20











22



71 Methods










decreased





23











24




Age (years)







25







731 Deaths




26












27








28












(056) 0

(051) 0

(057) 0



(256) 6

(351) 5

(357) 8



(056) 0

(051) 2

(157) 0

(052)




29










57 -66 50 +87 57 +134 52 +147





(181) 1

(189) 1

(189) 0



(381) 3

(388) 2

(289) 6


3 (281)

5 (489)

2 (288)

5 (485)


0 (057)

4 (250)

4 (257)

2 (152)


30






(ge200 mgdl) 4

(381) 12

(1189) 12

(1189) 11


(ge200 mgdl) 2

(160) 8

(452) 8

(560) 9

(553)








31












32







33








34







35













36









37







CWIT (msec) 17 +485 9 -195 19 -710 17 +243 LFT

( correct) 34 +17 27 +15 28 +06 32 +10

SFT ( correct)

33 +07 28 +23 25 +08 30 -16

ANS ( correct)

33 +04 28 +13 27 -02 31 +06


26 +39 24 -16 28 +45 27 +04




38
















39
















40




41













42










AST 80 -12 90 +06 90 +04 85 +34 ALT 80 -10 90 +13 90 +39 85 +88 GGT 80 -12 90 +04 90 +12 85 +22




43











44




45




46




47








743 Vital Signs





48




49






Day 14 +09 +21 +23 Day 21 +34 +31 +27




Day 14 +21 +28 +64 Day 21 +19 +10 +21



50





51








52













53




54




55







56






57












58







Female 2 21 169 0044 Male 11 16 17

Increased Appetite


Increased Appetite








59













60






61







0 10 (71) 10 (71) +1 3 (21) 3 (21) +2 1 (7) 1 (7)

Females (N=20)

Negative 0 1 (5) 0 14 (70) 13 (65)

+1 6 (30) 5 (25) +3 0 1 (5)

62









(b) (4)

(b) (4)

(b) (4)

(b) (4)



63




(b) (4)





9 Appendices



64






(b) (4)






65


---------------------------------------------------------------------------------------------------------

---------------------------------------------------------------------------------------------------------

----------------------------------------------------


s


JING ZHANG 02182015














Product Saphris





7



















8















9




















10



52 Review Strategy





611 Methods





11








12





612 Demographics





13









14







15





616 Other Endpoints





16




617 Subpopulations


17




18




19









(b) (4)

20











22



71 Methods










decreased





23











24




Age (years)







25







731 Deaths




26












27








28












(056) 0

(051) 0

(057) 0



(256) 6

(351) 5

(357) 8



(056) 0

(051) 2

(157) 0

(052)




29










57 -66 50 +87 57 +134 52 +147





(181) 1

(189) 1

(189) 0



(381) 3

(388) 2

(289) 6


3 (281)

5 (489)

2 (288)

5 (485)


0 (057)

4 (250)

4 (257)

2 (152)


30






(ge200 mgdl) 4

(381) 12

(1189) 12

(1189) 11


(ge200 mgdl) 2

(160) 8

(452) 8

(560) 9

(553)








31












32







33








34







35













36









37







CWIT (msec) 17 +485 9 -195 19 -710 17 +243 LFT

( correct) 34 +17 27 +15 28 +06 32 +10

SFT ( correct)

33 +07 28 +23 25 +08 30 -16

ANS ( correct)

33 +04 28 +13 27 -02 31 +06


26 +39 24 -16 28 +45 27 +04




38
















39
















40




41













42










AST 80 -12 90 +06 90 +04 85 +34 ALT 80 -10 90 +13 90 +39 85 +88 GGT 80 -12 90 +04 90 +12 85 +22




43











44




45




46




47








743 Vital Signs





48




49






Day 14 +09 +21 +23 Day 21 +34 +31 +27




Day 14 +21 +28 +64 Day 21 +19 +10 +21



50





51








52













53




54




55







56






57












58







Female 2 21 169 0044 Male 11 16 17

Increased Appetite


Increased Appetite








59













60






61







0 10 (71) 10 (71) +1 3 (21) 3 (21) +2 1 (7) 1 (7)

Females (N=20)

Negative 0 1 (5) 0 14 (70) 13 (65)

+1 6 (30) 5 (25) +3 0 1 (5)

62









(b) (4)

(b) (4)

(b) (4)

(b) (4)



63




(b) (4)





9 Appendices



64






(b) (4)






65


---------------------------------------------------------------------------------------------------------

---------------------------------------------------------------------------------------------------------

----------------------------------------------------


s


JING ZHANG 02182015



















8















9




















10



52 Review Strategy





611 Methods





11








12





612 Demographics





13









14







15





616 Other Endpoints





16




617 Subpopulations


17




18




19









(b) (4)

20











22



71 Methods










decreased





23











24




Age (years)







25







731 Deaths




26












27








28












(056) 0

(051) 0

(057) 0



(256) 6

(351) 5

(357) 8



(056) 0

(051) 2

(157) 0

(052)




29










57 -66 50 +87 57 +134 52 +147





(181) 1

(189) 1

(189) 0



(381) 3

(388) 2

(289) 6


3 (281)

5 (489)

2 (288)

5 (485)


0 (057)

4 (250)

4 (257)

2 (152)


30






(ge200 mgdl) 4

(381) 12

(1189) 12

(1189) 11


(ge200 mgdl) 2

(160) 8

(452) 8

(560) 9

(553)








31












32







33








34







35













36









37







CWIT (msec) 17 +485 9 -195 19 -710 17 +243 LFT

( correct) 34 +17 27 +15 28 +06 32 +10

SFT ( correct)

33 +07 28 +23 25 +08 30 -16

ANS ( correct)

33 +04 28 +13 27 -02 31 +06


26 +39 24 -16 28 +45 27 +04




38
















39
















40




41













42










AST 80 -12 90 +06 90 +04 85 +34 ALT 80 -10 90 +13 90 +39 85 +88 GGT 80 -12 90 +04 90 +12 85 +22




43











44




45




46




47








743 Vital Signs





48




49






Day 14 +09 +21 +23 Day 21 +34 +31 +27




Day 14 +21 +28 +64 Day 21 +19 +10 +21



50





51








52













53




54




55







56






57












58







Female 2 21 169 0044 Male 11 16 17

Increased Appetite


Increased Appetite








59













60






61







0 10 (71) 10 (71) +1 3 (21) 3 (21) +2 1 (7) 1 (7)

Females (N=20)

Negative 0 1 (5) 0 14 (70) 13 (65)

+1 6 (30) 5 (25) +3 0 1 (5)

62









(b) (4)

(b) (4)

(b) (4)

(b) (4)



63




(b) (4)





9 Appendices



64






(b) (4)






65


---------------------------------------------------------------------------------------------------------

---------------------------------------------------------------------------------------------------------

----------------------------------------------------


s


JING ZHANG 02182015















9




















10



52 Review Strategy





611 Methods





11








12





612 Demographics





13









14







15





616 Other Endpoints





16




617 Subpopulations


17




18




19









(b) (4)

20











22



71 Methods










decreased





23











24




Age (years)







25







731 Deaths




26












27








28












(056) 0

(051) 0

(057) 0



(256) 6

(351) 5

(357) 8



(056) 0

(051) 2

(157) 0

(052)




29










57 -66 50 +87 57 +134 52 +147





(181) 1

(189) 1

(189) 0



(381) 3

(388) 2

(289) 6


3 (281)

5 (489)

2 (288)

5 (485)


0 (057)

4 (250)

4 (257)

2 (152)


30






(ge200 mgdl) 4

(381) 12

(1189) 12

(1189) 11


(ge200 mgdl) 2

(160) 8

(452) 8

(560) 9

(553)








31












32







33








34







35













36









37







CWIT (msec) 17 +485 9 -195 19 -710 17 +243 LFT

( correct) 34 +17 27 +15 28 +06 32 +10

SFT ( correct)

33 +07 28 +23 25 +08 30 -16

ANS ( correct)

33 +04 28 +13 27 -02 31 +06


26 +39 24 -16 28 +45 27 +04




38
















39
















40




41













42










AST 80 -12 90 +06 90 +04 85 +34 ALT 80 -10 90 +13 90 +39 85 +88 GGT 80 -12 90 +04 90 +12 85 +22




43











44




45




46




47








743 Vital Signs





48




49






Day 14 +09 +21 +23 Day 21 +34 +31 +27




Day 14 +21 +28 +64 Day 21 +19 +10 +21



50





51








52













53




54




55







56






57












58







Female 2 21 169 0044 Male 11 16 17

Increased Appetite


Increased Appetite








59













60






61







0 10 (71) 10 (71) +1 3 (21) 3 (21) +2 1 (7) 1 (7)

Females (N=20)

Negative 0 1 (5) 0 14 (70) 13 (65)

+1 6 (30) 5 (25) +3 0 1 (5)

62









(b) (4)

(b) (4)

(b) (4)

(b) (4)



63




(b) (4)





9 Appendices



64






(b) (4)






65


---------------------------------------------------------------------------------------------------------

---------------------------------------------------------------------------------------------------------

----------------------------------------------------


s


JING ZHANG 02182015




















10



52 Review Strategy





611 Methods





11








12





612 Demographics





13









14







15





616 Other Endpoints





16




617 Subpopulations


17




18




19









(b) (4)

20











22



71 Methods










decreased





23











24




Age (years)







25







731 Deaths




26












27








28












(056) 0

(051) 0

(057) 0



(256) 6

(351) 5

(357) 8



(056) 0

(051) 2

(157) 0

(052)




29










57 -66 50 +87 57 +134 52 +147





(181) 1

(189) 1

(189) 0



(381) 3

(388) 2

(289) 6


3 (281)

5 (489)

2 (288)

5 (485)


0 (057)

4 (250)

4 (257)

2 (152)


30






(ge200 mgdl) 4

(381) 12

(1189) 12

(1189) 11


(ge200 mgdl) 2

(160) 8

(452) 8

(560) 9

(553)








31












32







33








34







35













36









37







CWIT (msec) 17 +485 9 -195 19 -710 17 +243 LFT

( correct) 34 +17 27 +15 28 +06 32 +10

SFT ( correct)

33 +07 28 +23 25 +08 30 -16

ANS ( correct)

33 +04 28 +13 27 -02 31 +06


26 +39 24 -16 28 +45 27 +04




38
















39
















40




41













42










AST 80 -12 90 +06 90 +04 85 +34 ALT 80 -10 90 +13 90 +39 85 +88 GGT 80 -12 90 +04 90 +12 85 +22




43











44




45




46




47








743 Vital Signs





48




49






Day 14 +09 +21 +23 Day 21 +34 +31 +27




Day 14 +21 +28 +64 Day 21 +19 +10 +21



50





51








52













53




54




55







56






57












58







Female 2 21 169 0044 Male 11 16 17

Increased Appetite


Increased Appetite








59













60






61







0 10 (71) 10 (71) +1 3 (21) 3 (21) +2 1 (7) 1 (7)

Females (N=20)

Negative 0 1 (5) 0 14 (70) 13 (65)

+1 6 (30) 5 (25) +3 0 1 (5)

62









(b) (4)

(b) (4)

(b) (4)

(b) (4)



63




(b) (4)





9 Appendices



64






(b) (4)






65


---------------------------------------------------------------------------------------------------------

---------------------------------------------------------------------------------------------------------

----------------------------------------------------


s


JING ZHANG 02182015



52 Review Strategy





611 Methods





11








12





612 Demographics





13









14







15





616 Other Endpoints





16




617 Subpopulations


17




18




19









(b) (4)

20











22



71 Methods










decreased





23











24




Age (years)







25







731 Deaths




26












27








28












(056) 0

(051) 0

(057) 0



(256) 6

(351) 5

(357) 8



(056) 0

(051) 2

(157) 0

(052)




29










57 -66 50 +87 57 +134 52 +147





(181) 1

(189) 1

(189) 0



(381) 3

(388) 2

(289) 6


3 (281)

5 (489)

2 (288)

5 (485)


0 (057)

4 (250)

4 (257)

2 (152)


30






(ge200 mgdl) 4

(381) 12

(1189) 12

(1189) 11


(ge200 mgdl) 2

(160) 8

(452) 8

(560) 9

(553)








31












32







33








34







35













36









37







CWIT (msec) 17 +485 9 -195 19 -710 17 +243 LFT

( correct) 34 +17 27 +15 28 +06 32 +10

SFT ( correct)

33 +07 28 +23 25 +08 30 -16

ANS ( correct)

33 +04 28 +13 27 -02 31 +06


26 +39 24 -16 28 +45 27 +04




38
















39
















40




41













42










AST 80 -12 90 +06 90 +04 85 +34 ALT 80 -10 90 +13 90 +39 85 +88 GGT 80 -12 90 +04 90 +12 85 +22




43











44




45




46




47








743 Vital Signs





48




49






Day 14 +09 +21 +23 Day 21 +34 +31 +27




Day 14 +21 +28 +64 Day 21 +19 +10 +21



50





51








52













53




54




55







56






57












58







Female 2 21 169 0044 Male 11 16 17

Increased Appetite


Increased Appetite








59













60






61







0 10 (71) 10 (71) +1 3 (21) 3 (21) +2 1 (7) 1 (7)

Females (N=20)

Negative 0 1 (5) 0 14 (70) 13 (65)

+1 6 (30) 5 (25) +3 0 1 (5)

62









(b) (4)

(b) (4)

(b) (4)

(b) (4)



63




(b) (4)





9 Appendices



64






(b) (4)






65


---------------------------------------------------------------------------------------------------------

---------------------------------------------------------------------------------------------------------

----------------------------------------------------


s


JING ZHANG 02182015








12





612 Demographics





13









14







15





616 Other Endpoints





16




617 Subpopulations


17




18




19









(b) (4)

20











22



71 Methods










decreased





23











24




Age (years)







25







731 Deaths




26












27








28












(056) 0

(051) 0

(057) 0



(256) 6

(351) 5

(357) 8



(056) 0

(051) 2

(157) 0

(052)




29










57 -66 50 +87 57 +134 52 +147





(181) 1

(189) 1

(189) 0



(381) 3

(388) 2

(289) 6


3 (281)

5 (489)

2 (288)

5 (485)


0 (057)

4 (250)

4 (257)

2 (152)


30






(ge200 mgdl) 4

(381) 12

(1189) 12

(1189) 11


(ge200 mgdl) 2

(160) 8

(452) 8

(560) 9

(553)








31












32







33








34







35













36









37







CWIT (msec) 17 +485 9 -195 19 -710 17 +243 LFT

( correct) 34 +17 27 +15 28 +06 32 +10

SFT ( correct)

33 +07 28 +23 25 +08 30 -16

ANS ( correct)

33 +04 28 +13 27 -02 31 +06


26 +39 24 -16 28 +45 27 +04




38
















39
















40




41













42










AST 80 -12 90 +06 90 +04 85 +34 ALT 80 -10 90 +13 90 +39 85 +88 GGT 80 -12 90 +04 90 +12 85 +22




43











44




45




46




47








743 Vital Signs





48




49






Day 14 +09 +21 +23 Day 21 +34 +31 +27




Day 14 +21 +28 +64 Day 21 +19 +10 +21



50





51








52













53




54




55







56






57












58







Female 2 21 169 0044 Male 11 16 17

Increased Appetite


Increased Appetite








59













60






61







0 10 (71) 10 (71) +1 3 (21) 3 (21) +2 1 (7) 1 (7)

Females (N=20)

Negative 0 1 (5) 0 14 (70) 13 (65)

+1 6 (30) 5 (25) +3 0 1 (5)

62









(b) (4)

(b) (4)

(b) (4)

(b) (4)



63




(b) (4)





9 Appendices



64






(b) (4)






65


---------------------------------------------------------------------------------------------------------

---------------------------------------------------------------------------------------------------------

----------------------------------------------------


s


JING ZHANG 02182015





612 Demographics





13









14







15





616 Other Endpoints





16




617 Subpopulations


17




18




19









(b) (4)

20











22



71 Methods










decreased





23











24




Age (years)







25







731 Deaths




26












27








28












(056) 0

(051) 0

(057) 0



(256) 6

(351) 5

(357) 8



(056) 0

(051) 2

(157) 0

(052)




29










57 -66 50 +87 57 +134 52 +147





(181) 1

(189) 1

(189) 0



(381) 3

(388) 2

(289) 6


3 (281)

5 (489)

2 (288)

5 (485)


0 (057)

4 (250)

4 (257)

2 (152)


30






(ge200 mgdl) 4

(381) 12

(1189) 12

(1189) 11


(ge200 mgdl) 2

(160) 8

(452) 8

(560) 9

(553)








31












32







33








34







35













36









37







CWIT (msec) 17 +485 9 -195 19 -710 17 +243 LFT

( correct) 34 +17 27 +15 28 +06 32 +10

SFT ( correct)

33 +07 28 +23 25 +08 30 -16

ANS ( correct)

33 +04 28 +13 27 -02 31 +06


26 +39 24 -16 28 +45 27 +04




38
















39
















40




41













42










AST 80 -12 90 +06 90 +04 85 +34 ALT 80 -10 90 +13 90 +39 85 +88 GGT 80 -12 90 +04 90 +12 85 +22




43











44




45




46




47








743 Vital Signs





48




49






Day 14 +09 +21 +23 Day 21 +34 +31 +27




Day 14 +21 +28 +64 Day 21 +19 +10 +21



50





51








52













53




54




55







56






57












58







Female 2 21 169 0044 Male 11 16 17

Increased Appetite


Increased Appetite








59













60






61







0 10 (71) 10 (71) +1 3 (21) 3 (21) +2 1 (7) 1 (7)

Females (N=20)

Negative 0 1 (5) 0 14 (70) 13 (65)

+1 6 (30) 5 (25) +3 0 1 (5)

62









(b) (4)

(b) (4)

(b) (4)

(b) (4)



63




(b) (4)





9 Appendices



64






(b) (4)






65


---------------------------------------------------------------------------------------------------------

---------------------------------------------------------------------------------------------------------

----------------------------------------------------


s


JING ZHANG 02182015









14







15





616 Other Endpoints





16




617 Subpopulations


17




18




19









(b) (4)

20











22



71 Methods










decreased





23











24




Age (years)







25







731 Deaths




26












27








28












(056) 0

(051) 0

(057) 0



(256) 6

(351) 5

(357) 8



(056) 0

(051) 2

(157) 0

(052)




29










57 -66 50 +87 57 +134 52 +147





(181) 1

(189) 1

(189) 0



(381) 3

(388) 2

(289) 6


3 (281)

5 (489)

2 (288)

5 (485)


0 (057)

4 (250)

4 (257)

2 (152)


30






(ge200 mgdl) 4

(381) 12

(1189) 12

(1189) 11


(ge200 mgdl) 2

(160) 8

(452) 8

(560) 9

(553)








31












32







33








34







35













36









37







CWIT (msec) 17 +485 9 -195 19 -710 17 +243 LFT

( correct) 34 +17 27 +15 28 +06 32 +10

SFT ( correct)

33 +07 28 +23 25 +08 30 -16

ANS ( correct)

33 +04 28 +13 27 -02 31 +06


26 +39 24 -16 28 +45 27 +04




38
















39
















40




41













42










AST 80 -12 90 +06 90 +04 85 +34 ALT 80 -10 90 +13 90 +39 85 +88 GGT 80 -12 90 +04 90 +12 85 +22




43











44




45




46




47








743 Vital Signs





48




49






Day 14 +09 +21 +23 Day 21 +34 +31 +27




Day 14 +21 +28 +64 Day 21 +19 +10 +21



50





51








52













53




54




55







56






57












58







Female 2 21 169 0044 Male 11 16 17

Increased Appetite


Increased Appetite








59













60






61







0 10 (71) 10 (71) +1 3 (21) 3 (21) +2 1 (7) 1 (7)

Females (N=20)

Negative 0 1 (5) 0 14 (70) 13 (65)

+1 6 (30) 5 (25) +3 0 1 (5)

62









(b) (4)

(b) (4)

(b) (4)

(b) (4)



63




(b) (4)





9 Appendices



64






(b) (4)






65


---------------------------------------------------------------------------------------------------------

---------------------------------------------------------------------------------------------------------

----------------------------------------------------


s


JING ZHANG 02182015







15





616 Other Endpoints





16




617 Subpopulations


17




18




19









(b) (4)

20











22



71 Methods










decreased





23











24




Age (years)







25







731 Deaths




26












27








28












(056) 0

(051) 0

(057) 0



(256) 6

(351) 5

(357) 8



(056) 0

(051) 2

(157) 0

(052)




29










57 -66 50 +87 57 +134 52 +147





(181) 1

(189) 1

(189) 0



(381) 3

(388) 2

(289) 6


3 (281)

5 (489)

2 (288)

5 (485)


0 (057)

4 (250)

4 (257)

2 (152)


30






(ge200 mgdl) 4

(381) 12

(1189) 12

(1189) 11


(ge200 mgdl) 2

(160) 8

(452) 8

(560) 9

(553)








31












32







33








34







35













36









37







CWIT (msec) 17 +485 9 -195 19 -710 17 +243 LFT

( correct) 34 +17 27 +15 28 +06 32 +10

SFT ( correct)

33 +07 28 +23 25 +08 30 -16

ANS ( correct)

33 +04 28 +13 27 -02 31 +06


26 +39 24 -16 28 +45 27 +04




38
















39
















40




41













42










AST 80 -12 90 +06 90 +04 85 +34 ALT 80 -10 90 +13 90 +39 85 +88 GGT 80 -12 90 +04 90 +12 85 +22




43











44




45




46




47








743 Vital Signs





48




49






Day 14 +09 +21 +23 Day 21 +34 +31 +27




Day 14 +21 +28 +64 Day 21 +19 +10 +21



50





51








52













53




54




55







56






57












58







Female 2 21 169 0044 Male 11 16 17

Increased Appetite


Increased Appetite








59













60






61







0 10 (71) 10 (71) +1 3 (21) 3 (21) +2 1 (7) 1 (7)

Females (N=20)

Negative 0 1 (5) 0 14 (70) 13 (65)

+1 6 (30) 5 (25) +3 0 1 (5)

62









(b) (4)

(b) (4)

(b) (4)

(b) (4)



63




(b) (4)





9 Appendices



64






(b) (4)






65


---------------------------------------------------------------------------------------------------------

---------------------------------------------------------------------------------------------------------

----------------------------------------------------


s


JING ZHANG 02182015





616 Other Endpoints





16




617 Subpopulations


17




18




19









(b) (4)

20











22



71 Methods










decreased





23











24




Age (years)







25







731 Deaths




26












27








28












(056) 0

(051) 0

(057) 0



(256) 6

(351) 5

(357) 8



(056) 0

(051) 2

(157) 0

(052)




29










57 -66 50 +87 57 +134 52 +147





(181) 1

(189) 1

(189) 0



(381) 3

(388) 2

(289) 6


3 (281)

5 (489)

2 (288)

5 (485)


0 (057)

4 (250)

4 (257)

2 (152)


30






(ge200 mgdl) 4

(381) 12

(1189) 12

(1189) 11


(ge200 mgdl) 2

(160) 8

(452) 8

(560) 9

(553)








31












32







33








34







35













36









37







CWIT (msec) 17 +485 9 -195 19 -710 17 +243 LFT

( correct) 34 +17 27 +15 28 +06 32 +10

SFT ( correct)

33 +07 28 +23 25 +08 30 -16

ANS ( correct)

33 +04 28 +13 27 -02 31 +06


26 +39 24 -16 28 +45 27 +04




38
















39
















40




41













42










AST 80 -12 90 +06 90 +04 85 +34 ALT 80 -10 90 +13 90 +39 85 +88 GGT 80 -12 90 +04 90 +12 85 +22




43











44




45




46




47








743 Vital Signs





48




49






Day 14 +09 +21 +23 Day 21 +34 +31 +27




Day 14 +21 +28 +64 Day 21 +19 +10 +21



50





51








52













53




54




55







56






57












58







Female 2 21 169 0044 Male 11 16 17

Increased Appetite


Increased Appetite








59













60






61







0 10 (71) 10 (71) +1 3 (21) 3 (21) +2 1 (7) 1 (7)

Females (N=20)

Negative 0 1 (5) 0 14 (70) 13 (65)

+1 6 (30) 5 (25) +3 0 1 (5)

62









(b) (4)

(b) (4)

(b) (4)

(b) (4)



63




(b) (4)





9 Appendices



64






(b) (4)






65


---------------------------------------------------------------------------------------------------------

---------------------------------------------------------------------------------------------------------

----------------------------------------------------


s


JING ZHANG 02182015




617 Subpopulations


17




18




19









(b) (4)

20











22



71 Methods










decreased





23











24




Age (years)







25







731 Deaths




26












27








28












(056) 0

(051) 0

(057) 0



(256) 6

(351) 5

(357) 8



(056) 0

(051) 2

(157) 0

(052)




29










57 -66 50 +87 57 +134 52 +147





(181) 1

(189) 1

(189) 0



(381) 3

(388) 2

(289) 6


3 (281)

5 (489)

2 (288)

5 (485)


0 (057)

4 (250)

4 (257)

2 (152)


30






(ge200 mgdl) 4

(381) 12

(1189) 12

(1189) 11


(ge200 mgdl) 2

(160) 8

(452) 8

(560) 9

(553)








31












32







33








34







35













36









37







CWIT (msec) 17 +485 9 -195 19 -710 17 +243 LFT

( correct) 34 +17 27 +15 28 +06 32 +10

SFT ( correct)

33 +07 28 +23 25 +08 30 -16

ANS ( correct)

33 +04 28 +13 27 -02 31 +06


26 +39 24 -16 28 +45 27 +04




38
















39
















40




41













42










AST 80 -12 90 +06 90 +04 85 +34 ALT 80 -10 90 +13 90 +39 85 +88 GGT 80 -12 90 +04 90 +12 85 +22




43











44




45




46




47








743 Vital Signs





48




49






Day 14 +09 +21 +23 Day 21 +34 +31 +27




Day 14 +21 +28 +64 Day 21 +19 +10 +21



50





51








52













53




54




55







56






57












58







Female 2 21 169 0044 Male 11 16 17

Increased Appetite


Increased Appetite








59













60






61







0 10 (71) 10 (71) +1 3 (21) 3 (21) +2 1 (7) 1 (7)

Females (N=20)

Negative 0 1 (5) 0 14 (70) 13 (65)

+1 6 (30) 5 (25) +3 0 1 (5)

62









(b) (4)

(b) (4)

(b) (4)

(b) (4)



63




(b) (4)





9 Appendices



64






(b) (4)






65


---------------------------------------------------------------------------------------------------------

---------------------------------------------------------------------------------------------------------

----------------------------------------------------


s


JING ZHANG 02182015




18




19









(b) (4)

20











22



71 Methods










decreased





23











24




Age (years)







25







731 Deaths




26












27








28












(056) 0

(051) 0

(057) 0



(256) 6

(351) 5

(357) 8



(056) 0

(051) 2

(157) 0

(052)




29










57 -66 50 +87 57 +134 52 +147





(181) 1

(189) 1

(189) 0



(381) 3

(388) 2

(289) 6


3 (281)

5 (489)

2 (288)

5 (485)


0 (057)

4 (250)

4 (257)

2 (152)


30






(ge200 mgdl) 4

(381) 12

(1189) 12

(1189) 11


(ge200 mgdl) 2

(160) 8

(452) 8

(560) 9

(553)








31












32







33








34







35













36









37







CWIT (msec) 17 +485 9 -195 19 -710 17 +243 LFT

( correct) 34 +17 27 +15 28 +06 32 +10

SFT ( correct)

33 +07 28 +23 25 +08 30 -16

ANS ( correct)

33 +04 28 +13 27 -02 31 +06


26 +39 24 -16 28 +45 27 +04




38
















39
















40




41













42










AST 80 -12 90 +06 90 +04 85 +34 ALT 80 -10 90 +13 90 +39 85 +88 GGT 80 -12 90 +04 90 +12 85 +22




43











44




45




46




47








743 Vital Signs





48




49






Day 14 +09 +21 +23 Day 21 +34 +31 +27




Day 14 +21 +28 +64 Day 21 +19 +10 +21



50





51








52













53




54




55







56






57












58







Female 2 21 169 0044 Male 11 16 17

Increased Appetite


Increased Appetite








59













60






61







0 10 (71) 10 (71) +1 3 (21) 3 (21) +2 1 (7) 1 (7)

Females (N=20)

Negative 0 1 (5) 0 14 (70) 13 (65)

+1 6 (30) 5 (25) +3 0 1 (5)

62









(b) (4)

(b) (4)

(b) (4)

(b) (4)



63




(b) (4)





9 Appendices



64






(b) (4)






65


---------------------------------------------------------------------------------------------------------

---------------------------------------------------------------------------------------------------------

----------------------------------------------------


s


JING ZHANG 02182015




19









(b) (4)

20











22



71 Methods










decreased





23











24




Age (years)







25







731 Deaths




26












27








28












(056) 0

(051) 0

(057) 0



(256) 6

(351) 5

(357) 8



(056) 0

(051) 2

(157) 0

(052)




29










57 -66 50 +87 57 +134 52 +147





(181) 1

(189) 1

(189) 0



(381) 3

(388) 2

(289) 6


3 (281)

5 (489)

2 (288)

5 (485)


0 (057)

4 (250)

4 (257)

2 (152)


30






(ge200 mgdl) 4

(381) 12

(1189) 12

(1189) 11


(ge200 mgdl) 2

(160) 8

(452) 8

(560) 9

(553)








31












32







33








34







35













36









37







CWIT (msec) 17 +485 9 -195 19 -710 17 +243 LFT

( correct) 34 +17 27 +15 28 +06 32 +10

SFT ( correct)

33 +07 28 +23 25 +08 30 -16

ANS ( correct)

33 +04 28 +13 27 -02 31 +06


26 +39 24 -16 28 +45 27 +04




38
















39
















40




41













42










AST 80 -12 90 +06 90 +04 85 +34 ALT 80 -10 90 +13 90 +39 85 +88 GGT 80 -12 90 +04 90 +12 85 +22




43











44




45




46




47








743 Vital Signs





48




49






Day 14 +09 +21 +23 Day 21 +34 +31 +27




Day 14 +21 +28 +64 Day 21 +19 +10 +21



50





51








52













53




54




55







56






57












58







Female 2 21 169 0044 Male 11 16 17

Increased Appetite


Increased Appetite








59













60






61







0 10 (71) 10 (71) +1 3 (21) 3 (21) +2 1 (7) 1 (7)

Females (N=20)

Negative 0 1 (5) 0 14 (70) 13 (65)

+1 6 (30) 5 (25) +3 0 1 (5)

62









(b) (4)

(b) (4)

(b) (4)

(b) (4)



63




(b) (4)





9 Appendices



64






(b) (4)






65


---------------------------------------------------------------------------------------------------------

---------------------------------------------------------------------------------------------------------

----------------------------------------------------


s


JING ZHANG 02182015









(b) (4)

20











22



71 Methods










decreased





23











24




Age (years)







25







731 Deaths




26












27








28












(056) 0

(051) 0

(057) 0



(256) 6

(351) 5

(357) 8



(056) 0

(051) 2

(157) 0

(052)




29










57 -66 50 +87 57 +134 52 +147





(181) 1

(189) 1

(189) 0



(381) 3

(388) 2

(289) 6


3 (281)

5 (489)

2 (288)

5 (485)


0 (057)

4 (250)

4 (257)

2 (152)


30






(ge200 mgdl) 4

(381) 12

(1189) 12

(1189) 11


(ge200 mgdl) 2

(160) 8

(452) 8

(560) 9

(553)








31












32







33








34







35













36









37







CWIT (msec) 17 +485 9 -195 19 -710 17 +243 LFT

( correct) 34 +17 27 +15 28 +06 32 +10

SFT ( correct)

33 +07 28 +23 25 +08 30 -16

ANS ( correct)

33 +04 28 +13 27 -02 31 +06


26 +39 24 -16 28 +45 27 +04




38
















39
















40




41













42










AST 80 -12 90 +06 90 +04 85 +34 ALT 80 -10 90 +13 90 +39 85 +88 GGT 80 -12 90 +04 90 +12 85 +22




43











44




45




46




47








743 Vital Signs





48




49






Day 14 +09 +21 +23 Day 21 +34 +31 +27




Day 14 +21 +28 +64 Day 21 +19 +10 +21



50





51








52













53




54




55







56






57












58







Female 2 21 169 0044 Male 11 16 17

Increased Appetite


Increased Appetite








59













60






61







0 10 (71) 10 (71) +1 3 (21) 3 (21) +2 1 (7) 1 (7)

Females (N=20)

Negative 0 1 (5) 0 14 (70) 13 (65)

+1 6 (30) 5 (25) +3 0 1 (5)

62









(b) (4)

(b) (4)

(b) (4)

(b) (4)



63




(b) (4)





9 Appendices



64






(b) (4)






65


---------------------------------------------------------------------------------------------------------

---------------------------------------------------------------------------------------------------------

----------------------------------------------------


s


JING ZHANG 02182015











22



71 Methods










decreased





23











24




Age (years)







25







731 Deaths




26












27








28












(056) 0

(051) 0

(057) 0



(256) 6

(351) 5

(357) 8



(056) 0

(051) 2

(157) 0

(052)




29










57 -66 50 +87 57 +134 52 +147





(181) 1

(189) 1

(189) 0



(381) 3

(388) 2

(289) 6


3 (281)

5 (489)

2 (288)

5 (485)


0 (057)

4 (250)

4 (257)

2 (152)


30






(ge200 mgdl) 4

(381) 12

(1189) 12

(1189) 11


(ge200 mgdl) 2

(160) 8

(452) 8

(560) 9

(553)








31












32







33








34







35













36









37







CWIT (msec) 17 +485 9 -195 19 -710 17 +243 LFT

( correct) 34 +17 27 +15 28 +06 32 +10

SFT ( correct)

33 +07 28 +23 25 +08 30 -16

ANS ( correct)

33 +04 28 +13 27 -02 31 +06


26 +39 24 -16 28 +45 27 +04




38
















39
















40




41













42










AST 80 -12 90 +06 90 +04 85 +34 ALT 80 -10 90 +13 90 +39 85 +88 GGT 80 -12 90 +04 90 +12 85 +22




43











44




45




46




47








743 Vital Signs





48




49






Day 14 +09 +21 +23 Day 21 +34 +31 +27




Day 14 +21 +28 +64 Day 21 +19 +10 +21



50





51








52













53




54




55







56






57












58







Female 2 21 169 0044 Male 11 16 17

Increased Appetite


Increased Appetite








59













60






61







0 10 (71) 10 (71) +1 3 (21) 3 (21) +2 1 (7) 1 (7)

Females (N=20)

Negative 0 1 (5) 0 14 (70) 13 (65)

+1 6 (30) 5 (25) +3 0 1 (5)

62









(b) (4)

(b) (4)

(b) (4)

(b) (4)



63




(b) (4)





9 Appendices



64






(b) (4)






65


---------------------------------------------------------------------------------------------------------

---------------------------------------------------------------------------------------------------------

----------------------------------------------------


s


JING ZHANG 02182015



71 Methods










decreased





23











24




Age (years)







25







731 Deaths




26












27








28












(056) 0

(051) 0

(057) 0



(256) 6

(351) 5

(357) 8



(056) 0

(051) 2

(157) 0

(052)




29










57 -66 50 +87 57 +134 52 +147





(181) 1

(189) 1

(189) 0



(381) 3

(388) 2

(289) 6


3 (281)

5 (489)

2 (288)

5 (485)


0 (057)

4 (250)

4 (257)

2 (152)


30






(ge200 mgdl) 4

(381) 12

(1189) 12

(1189) 11


(ge200 mgdl) 2

(160) 8

(452) 8

(560) 9

(553)








31












32







33








34







35













36









37







CWIT (msec) 17 +485 9 -195 19 -710 17 +243 LFT

( correct) 34 +17 27 +15 28 +06 32 +10

SFT ( correct)

33 +07 28 +23 25 +08 30 -16

ANS ( correct)

33 +04 28 +13 27 -02 31 +06


26 +39 24 -16 28 +45 27 +04




38
















39
















40




41













42










AST 80 -12 90 +06 90 +04 85 +34 ALT 80 -10 90 +13 90 +39 85 +88 GGT 80 -12 90 +04 90 +12 85 +22




43











44




45




46




47








743 Vital Signs





48




49






Day 14 +09 +21 +23 Day 21 +34 +31 +27




Day 14 +21 +28 +64 Day 21 +19 +10 +21



50





51








52













53




54




55







56






57












58







Female 2 21 169 0044 Male 11 16 17

Increased Appetite


Increased Appetite








59













60






61







0 10 (71) 10 (71) +1 3 (21) 3 (21) +2 1 (7) 1 (7)

Females (N=20)

Negative 0 1 (5) 0 14 (70) 13 (65)

+1 6 (30) 5 (25) +3 0 1 (5)

62









(b) (4)

(b) (4)

(b) (4)

(b) (4)



63




(b) (4)





9 Appendices



64






(b) (4)






65


---------------------------------------------------------------------------------------------------------

---------------------------------------------------------------------------------------------------------

----------------------------------------------------


s


JING ZHANG 02182015











24




Age (years)







25







731 Deaths




26












27








28












(056) 0

(051) 0

(057) 0



(256) 6

(351) 5

(357) 8



(056) 0

(051) 2

(157) 0

(052)




29










57 -66 50 +87 57 +134 52 +147





(181) 1

(189) 1

(189) 0



(381) 3

(388) 2

(289) 6


3 (281)

5 (489)

2 (288)

5 (485)


0 (057)

4 (250)

4 (257)

2 (152)


30






(ge200 mgdl) 4

(381) 12

(1189) 12

(1189) 11


(ge200 mgdl) 2

(160) 8

(452) 8

(560) 9

(553)








31












32







33








34







35













36









37







CWIT (msec) 17 +485 9 -195 19 -710 17 +243 LFT

( correct) 34 +17 27 +15 28 +06 32 +10

SFT ( correct)

33 +07 28 +23 25 +08 30 -16

ANS ( correct)

33 +04 28 +13 27 -02 31 +06


26 +39 24 -16 28 +45 27 +04




38
















39
















40




41













42










AST 80 -12 90 +06 90 +04 85 +34 ALT 80 -10 90 +13 90 +39 85 +88 GGT 80 -12 90 +04 90 +12 85 +22




43











44




45




46




47








743 Vital Signs





48




49






Day 14 +09 +21 +23 Day 21 +34 +31 +27




Day 14 +21 +28 +64 Day 21 +19 +10 +21



50





51








52













53




54




55







56






57












58







Female 2 21 169 0044 Male 11 16 17

Increased Appetite


Increased Appetite








59













60






61







0 10 (71) 10 (71) +1 3 (21) 3 (21) +2 1 (7) 1 (7)

Females (N=20)

Negative 0 1 (5) 0 14 (70) 13 (65)

+1 6 (30) 5 (25) +3 0 1 (5)

62









(b) (4)

(b) (4)

(b) (4)

(b) (4)



63




(b) (4)





9 Appendices



64






(b) (4)






65


---------------------------------------------------------------------------------------------------------

---------------------------------------------------------------------------------------------------------

----------------------------------------------------


s


JING ZHANG 02182015




Age (years)







25







731 Deaths




26












27








28












(056) 0

(051) 0

(057) 0



(256) 6

(351) 5

(357) 8



(056) 0

(051) 2

(157) 0

(052)




29










57 -66 50 +87 57 +134 52 +147





(181) 1

(189) 1

(189) 0



(381) 3

(388) 2

(289) 6


3 (281)

5 (489)

2 (288)

5 (485)


0 (057)

4 (250)

4 (257)

2 (152)


30






(ge200 mgdl) 4

(381) 12

(1189) 12

(1189) 11


(ge200 mgdl) 2

(160) 8

(452) 8

(560) 9

(553)








31












32







33








34







35













36









37







CWIT (msec) 17 +485 9 -195 19 -710 17 +243 LFT

( correct) 34 +17 27 +15 28 +06 32 +10

SFT ( correct)

33 +07 28 +23 25 +08 30 -16

ANS ( correct)

33 +04 28 +13 27 -02 31 +06


26 +39 24 -16 28 +45 27 +04




38
















39
















40




41













42










AST 80 -12 90 +06 90 +04 85 +34 ALT 80 -10 90 +13 90 +39 85 +88 GGT 80 -12 90 +04 90 +12 85 +22




43











44




45




46




47








743 Vital Signs





48




49






Day 14 +09 +21 +23 Day 21 +34 +31 +27




Day 14 +21 +28 +64 Day 21 +19 +10 +21



50





51








52













53




54




55







56






57












58







Female 2 21 169 0044 Male 11 16 17

Increased Appetite


Increased Appetite








59













60






61







0 10 (71) 10 (71) +1 3 (21) 3 (21) +2 1 (7) 1 (7)

Females (N=20)

Negative 0 1 (5) 0 14 (70) 13 (65)

+1 6 (30) 5 (25) +3 0 1 (5)

62









(b) (4)

(b) (4)

(b) (4)

(b) (4)



63




(b) (4)





9 Appendices



64






(b) (4)






65


---------------------------------------------------------------------------------------------------------

---------------------------------------------------------------------------------------------------------

----------------------------------------------------


s


JING ZHANG 02182015







731 Deaths




26












27








28












(056) 0

(051) 0

(057) 0



(256) 6

(351) 5

(357) 8



(056) 0

(051) 2

(157) 0

(052)




29










57 -66 50 +87 57 +134 52 +147





(181) 1

(189) 1

(189) 0



(381) 3

(388) 2

(289) 6


3 (281)

5 (489)

2 (288)

5 (485)


0 (057)

4 (250)

4 (257)

2 (152)


30






(ge200 mgdl) 4

(381) 12

(1189) 12

(1189) 11


(ge200 mgdl) 2

(160) 8

(452) 8

(560) 9

(553)








31












32







33








34







35













36









37







CWIT (msec) 17 +485 9 -195 19 -710 17 +243 LFT

( correct) 34 +17 27 +15 28 +06 32 +10

SFT ( correct)

33 +07 28 +23 25 +08 30 -16

ANS ( correct)

33 +04 28 +13 27 -02 31 +06


26 +39 24 -16 28 +45 27 +04




38
















39
















40




41













42










AST 80 -12 90 +06 90 +04 85 +34 ALT 80 -10 90 +13 90 +39 85 +88 GGT 80 -12 90 +04 90 +12 85 +22




43











44




45




46




47








743 Vital Signs





48




49






Day 14 +09 +21 +23 Day 21 +34 +31 +27




Day 14 +21 +28 +64 Day 21 +19 +10 +21



50





51








52













53




54




55







56






57












58







Female 2 21 169 0044 Male 11 16 17

Increased Appetite


Increased Appetite








59













60






61







0 10 (71) 10 (71) +1 3 (21) 3 (21) +2 1 (7) 1 (7)

Females (N=20)

Negative 0 1 (5) 0 14 (70) 13 (65)

+1 6 (30) 5 (25) +3 0 1 (5)

62









(b) (4)

(b) (4)

(b) (4)

(b) (4)



63




(b) (4)





9 Appendices



64






(b) (4)






65


---------------------------------------------------------------------------------------------------------

---------------------------------------------------------------------------------------------------------

----------------------------------------------------


s


JING ZHANG 02182015












27








28












(056) 0

(051) 0

(057) 0



(256) 6

(351) 5

(357) 8



(056) 0

(051) 2

(157) 0

(052)




29










57 -66 50 +87 57 +134 52 +147





(181) 1

(189) 1

(189) 0



(381) 3

(388) 2

(289) 6


3 (281)

5 (489)

2 (288)

5 (485)


0 (057)

4 (250)

4 (257)

2 (152)


30






(ge200 mgdl) 4

(381) 12

(1189) 12

(1189) 11


(ge200 mgdl) 2

(160) 8

(452) 8

(560) 9

(553)








31












32







33








34







35













36









37







CWIT (msec) 17 +485 9 -195 19 -710 17 +243 LFT

( correct) 34 +17 27 +15 28 +06 32 +10

SFT ( correct)

33 +07 28 +23 25 +08 30 -16

ANS ( correct)

33 +04 28 +13 27 -02 31 +06


26 +39 24 -16 28 +45 27 +04




38
















39
















40




41













42










AST 80 -12 90 +06 90 +04 85 +34 ALT 80 -10 90 +13 90 +39 85 +88 GGT 80 -12 90 +04 90 +12 85 +22




43











44




45




46




47








743 Vital Signs





48




49






Day 14 +09 +21 +23 Day 21 +34 +31 +27




Day 14 +21 +28 +64 Day 21 +19 +10 +21



50





51








52













53




54




55







56






57












58







Female 2 21 169 0044 Male 11 16 17

Increased Appetite


Increased Appetite








59













60






61







0 10 (71) 10 (71) +1 3 (21) 3 (21) +2 1 (7) 1 (7)

Females (N=20)

Negative 0 1 (5) 0 14 (70) 13 (65)

+1 6 (30) 5 (25) +3 0 1 (5)

62









(b) (4)

(b) (4)

(b) (4)

(b) (4)



63




(b) (4)





9 Appendices



64






(b) (4)






65


---------------------------------------------------------------------------------------------------------

---------------------------------------------------------------------------------------------------------

----------------------------------------------------


s


JING ZHANG 02182015








28












(056) 0

(051) 0

(057) 0



(256) 6

(351) 5

(357) 8



(056) 0

(051) 2

(157) 0

(052)




29










57 -66 50 +87 57 +134 52 +147





(181) 1

(189) 1

(189) 0



(381) 3

(388) 2

(289) 6


3 (281)

5 (489)

2 (288)

5 (485)


0 (057)

4 (250)

4 (257)

2 (152)


30






(ge200 mgdl) 4

(381) 12

(1189) 12

(1189) 11


(ge200 mgdl) 2

(160) 8

(452) 8

(560) 9

(553)








31












32







33








34







35













36









37







CWIT (msec) 17 +485 9 -195 19 -710 17 +243 LFT

( correct) 34 +17 27 +15 28 +06 32 +10

SFT ( correct)

33 +07 28 +23 25 +08 30 -16

ANS ( correct)

33 +04 28 +13 27 -02 31 +06


26 +39 24 -16 28 +45 27 +04




38
















39
















40




41













42










AST 80 -12 90 +06 90 +04 85 +34 ALT 80 -10 90 +13 90 +39 85 +88 GGT 80 -12 90 +04 90 +12 85 +22




43











44




45




46




47








743 Vital Signs





48




49






Day 14 +09 +21 +23 Day 21 +34 +31 +27




Day 14 +21 +28 +64 Day 21 +19 +10 +21



50





51








52













53




54




55







56






57












58







Female 2 21 169 0044 Male 11 16 17

Increased Appetite


Increased Appetite








59













60






61







0 10 (71) 10 (71) +1 3 (21) 3 (21) +2 1 (7) 1 (7)

Females (N=20)

Negative 0 1 (5) 0 14 (70) 13 (65)

+1 6 (30) 5 (25) +3 0 1 (5)

62









(b) (4)

(b) (4)

(b) (4)

(b) (4)



63




(b) (4)





9 Appendices



64






(b) (4)






65


---------------------------------------------------------------------------------------------------------

---------------------------------------------------------------------------------------------------------

----------------------------------------------------


s


JING ZHANG 02182015


Date post:	10-Aug-2021
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N22-117S018; S019 Asenapine Clinical BPCA · 2015. 1. 8. · • P06107-0018-100475. 6 Reference...

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